US20050096376A1 - Substituted 3-pyrrolidine-indole derivatives - Google Patents

Substituted 3-pyrrolidine-indole derivatives Download PDF

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US20050096376A1
US20050096376A1 US10/916,633 US91663304A US2005096376A1 US 20050096376 A1 US20050096376 A1 US 20050096376A1 US 91663304 A US91663304 A US 91663304A US 2005096376 A1 US2005096376 A1 US 2005096376A1
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pyrrolidin
indol
phenyl
methanone
benzyl
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Corinna Sundermann
Bernd Sundermann
Edward Bijsterveld
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Gruenenthal GmbH
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

  • the invention relates to substituted 3-pyrrolidine-indole derivatives, to methods for their production, to pharmaceutical compositions containing these compounds and to the use of these substances for producing pharmaceutical compositions, and to related treatment methods including methods for treating pain and/or depression.
  • Depression is an affectivity disorder, in which a depressive syndrome predominates, depressive being associated with a low feeling or denoting a sad disposition.
  • the anti-depressants used for therapy are also important adjuvants for pain therapy (in Analgesics—from Chemistry and Pharmacology to Clinical Application, 265-284, Wiley VCH, 2002), in particular for chronic pain, as the prolonged stress of pain may lead to a depressive mood in the patient. This is often the case with patients suffering from pain with cancer (Berard, Int. Med. J. 1996, 3/4 257-259).
  • the anti-depressants have to be added as a medication supplementary to the analgesic dose.
  • the additional dose of the anti-depressant leads to further stressing of the organism. For this reason and to increase acceptance, an analgesically effective substance with an anti-depressive active component would be particularly advantageous.
  • the basis of the anti-depressive efficacy is the reuptake inhibition of serotonin.
  • WO9311106 describes 5-substituted 3-pyrrolidine-indole derivatives, wherein the radical on the pyrrolidine nitrogen represents an alkyl chain or aryl.
  • WO02051837 describes 3-pyrrolidine-indole derivatives as 5-HT 6 ligands, wherein the radical on the pyrrolidine nitrogen represents an alkyl chain, in which one carbon may also be replaced by oxygen or nitrogen, cycloalkyl, cycloheteroaryl, aryl or heteroaryl.
  • WO9410171 discloses 3-pyrrolidine-indole derivatives with alkyl, aryl and alkyl aryl as nitrogen substituents of the pyrrolidine as analgesically effective compounds which, however, are substituted in the 5 position.
  • U.S. Pat. No. 3,109,844 discloses 3-pyrrolidine-indole derivatives which carry a substituted alkyl radical on the pyrrolidine nitrogen.
  • WO02079190 describes 3-pyrrolidine-indole derivatives which carry a specifically substituted alkyl radical (a saturated nitrogen heterocycle) on the pyrrolidine nitrogen. These 3-pyrrolidine-indole derivatives are chemokine antagonists.
  • WO02079151 describes 3-pyrrolidine-indole derivatives which have an alkyl chain on the pyrrolidine nitrogen, which may be interrupted by a cyclic radical, these derivatives being chemokine antagonists.
  • WO0214317 discloses 3-pyrrolidine-indole derivatives, wherein a pyrazole radical is linked via an alkyl chain, which chain may also contain heteroatoms, to the pyrrolidine nitrogen.
  • WO0143740 discloses 3-pyrrolidine-indole derivatives, wherein an aryl radical is linked via an alkyl chain, which is interrupted by a heteroatom, to the pyrrolidine nitrogen.
  • WO9958525 and WO9910346 disclose 3-pyrrolidine-indole derivatives, wherein a dihydroindole radical or 3,4-dihydro-1H-benzo[1,2,6]thiadiazine-2,2-dioxide is linked via an alkyl chain to the pyrrolidine nitrogen.
  • U.S. Pat. No. 5,792,760 discloses 3-pyrrolidine-indole derivatives, wherein a N-benzyl-N-(3-1H-indol-3-yl-propionyl)-acetamide radical is linked via an ethylamine group to the pyrrolidine nitrogen.
  • WO9740038 discloses compounds, wherein the pyrrolidine nitrogen is linked to an alkyl chain or a cycloalkyl ring, a phenyl radical or a nitrogen substituent via an alkylamine chain, an alkylamide chain or an amide function.
  • One object of the invention was to make available a new structural class of anti-depressant substances which are also capable, in particular, of treating pain.
  • substituted 3-pyrrolidine-indole derivatives of general formula I which in addition to serotonin reuptake inhibition also exhibit noradrenalin reuptake inhibition and a sodium channel bond (BTX binding site), and have a pronounced anti-depressive and also analgesic effect.
  • substituted 3-pyrrolidine-indole derivatives wherein the radical R 1 represents H; respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C 1-8 -alkyl; respectively singly or multiply substituted or unsubstituted benzyl or methylnaphthyl, particularly preferred being benzyl which is unsubstituted or singly or multiply substituted by CF 3 , Br, F, CN, OCH 3 or CH 3 ; CH 2 CONR 3 R 4 and the remaining radicals have the meaning given above are preferred.
  • substituted 3-pyrrolidine-indole derivates wherein the radical R 2 represents CH 2 COR 9 and R 9 represents 2,5-dimethylpyrazole, 3-cyano-4-methylthiophene, 4-trifluoromethylphenyl, 4-phenyl-5-trifluoromethylthiophene and the remaining radicals have the meaning given above are also preferred.
  • substituted 3-pyrrolidine-indole derivates selected from the group comprising
  • C 1-8 alkyl and “C 1-3 alkyl” include acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight-chained and unsubstituted or singly or multiply substituted, by 1 to 8 or 1 to 3 carbon atoms, i.e. C 1-8 alkanyls, C 2-8 alkenyls and C 2-8 alkinyls or C 1-3 alkanyls, C 2-3 alkenyls and alkinyls.
  • Alkenyls have at least one C—C double bond and alkinyls at least one C—C triple bond.
  • Alkyl is advantageously selected from the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, 2-hexyl, n-heptyl, n-octyl, 1,1,3,3-tetramethylbutyl; ethylenyl (vinyl), ethinyl, propenyl (—CH 2 CH ⁇ CH 2 , —CH ⁇ CH—CH 3 , —C( ⁇ CH 2 )—CH 3 ), propinyl (—CH—C ⁇ CH), butenyl, butinyl, pentenyl, pentinyl, hexenyl, hexinyl, heptenyl, heptinyl, octeny
  • C 3-8 cycloalkyl represents for the purposes of this invention, cyclic hydrocarbons with 3 to 8 carbon atoms, which may be saturated or unsaturated, unsubstituted or singly or multiply substituted.
  • C 3-8 cycloalkyl is advantageously selected from the group comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl und cyclooctenyl.
  • Cycloalkyl particularly preferably represents cyclohexyl, cyclopentyl and cyclobutyl.
  • heterocyclyl represents a 3-, 4-, 5-, 6- or 7-membered cyclic organic radical containing at least 1, possibly also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms may be the same or different and the cyclic radical may be saturated or unsaturated, but is not aromatic, and may be unsubstituted or singly or multiply substituted.
  • the heterocycle may also be part of a bicyclic or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulphur.
  • heterocyclyl radical is selected from the group comprising tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein the bond with the compound of general structure I may be made by any ring member of the heterocyclyl radical.
  • aryl represents aromatic hydrocarbons, inter alia phenyls, naphthyls and phenanthracenyls.
  • the aryl radicals may also be condensed with further saturated, (partially) unsaturated or aromatic ring systems.
  • Each aryl radical may be present in an unsubstituted or singly or multiply substituted form, wherein the aryl substituents may be the same or different and in any arbitrary and possible position of the aryl.
  • Aryl is advantageously selected from the group comprising phenyl, 1-naphthyl and 2-naphthyl which may each be unsubstituted or singly or multiply substituted.
  • heteroaryl represents a 5-, 6- or 7-membered cyclic aromatic radical which contains at least 1, possibly also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms may be the same or different and the heterocycle may be unsubstituted or singly or multiply substituted; in the case of substitution on the heterocycle the heteroaryl substituents may be the same or different and in any position of the heteroaryl.
  • the heterocycle may also be part of a bicyclic or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulphur.
  • the heteroaryl radical is selected from the group comprising pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, pyrazolyl, imidazolyl, chromenyl, oxadiazolyl, thiazolyl, oxazolyl, isoxazoyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indolyl, indazolyl, purinyl, pyrimidinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, wherein the bond with the compounds of general structure I may be made by any arbitrary and possible ring member of the heteroaryl radical.
  • aryl bound via C 1-3 -alkyl, C 3-8 -cycloalkyl or heteroaryl means that C 1-3 alkyl and C 3-8 -cycloalkyl, aryl and heteroaryl have the meanings defined above and the cycloalkyl, aryl or heteroaryl radical is bound by a C 1-3 alkyl group to the compound of general structure I.
  • alkyl In conjunction with “alkyl”, “alkanyl”, “alkenyl” and “alkinyl”, the term “substituted” is taken to mean, according to this invention, the substitution of a hydrogen radical by F, Cl, Br, I, —CN, —N ⁇ C, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-heterocyclyl, NH-alkyl-OH, N(alkyl) 2 , N(alkyl-aryl) 2 , N(alkyl-heteroaryl) 2 , N(heterocyclyl) 2 , N(alkyl-OH) 2 , NO, NO 2 , SH, S-alkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-he
  • O-alkyl also comprises inter alia —O—CH 2 —CH 2 —O—CH 2 —CH 2 —OH.
  • alkyl particularly preferably represents methyl, ethyl, propyl, —OCH 3 or —CN.
  • aryl “heterocyclyl”, “heteroaryl” “cycloalkyl”, according to this invention “singly or multiply substituted” is taken to mean the single or multiple, for example double, triple or fourfold, substitution of one or more hydrogen atoms of the ring system by F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-heterocyclyl, NH-alkyl-OH, N(alkyl) 2 , N(alkyl-aryl) 2 , N(alkyl-heteroaryl) 2 , N(heterocyclyl) 2 , N(alkyl-OH) 2 , NO, NO 2 , SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-
  • substituents for “aryl” are —F, —Cl, —Br, —CF 3 , —O—CH 3 , —O—CH 2 CH 3 , methyl, n-propyl, nitro, tert.-butyl, —CN, —SCF 3 , phenyl and —SCHF 2 .
  • Particularly preferred substituents for “heteroaryl” are methyl, —CF 3 , phenyl, 2-chlorophenyl, 4-chlorophenyl, —SCH 3 , —Cl, —CN, n-propyl and tert.butyl.
  • —Cl is a preferred substituent for “heterocyclyl”.
  • the term salt formed with a physiologically acceptable acid refers to salts of the respective active ingredient with inorganic or organic acids which are physiologically acceptable—in particular when applied to humans and/or mammals.
  • Hydrochloride is particularly preferred.
  • physiologically acceptable acids are: hydrochloric acid, hydrobromic acid, sulphuric acid, methane sulphonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydrol ⁇ 6 -benzo[d]isothiazol-3-one (saccharic acid), monomethyl sebacic acid, 5-oxo-proline, hexane-l-sulphonic acid, nicotinic acid, 2-, 3- or 4-amino benzoic acid, 2,4,6-trimethyl-benzoic acid, a-lipoic acid, acety
  • the substances according to the invention are suitable as pharmaceutical active ingredients in pharmaceutical compositions.
  • the invention therefore also relates to pharmaceutical compositions containing at least one 3-pyrrolidine-indole derivative according to the invention and to optionally suitable additives and/or auxiliaries and/or optionally further active ingredients.
  • compositions according to the invention contain, in addition to at least one substituted 3-pyrrolidine-indole derivative according to the invention, optionally suitable additives and/or auxiliary agents, therefore also excipients, fillers, solvents, diluents, dyes and/or binders and may be administered as liquid pharmaceutical preparations in the form of injection solutions, drops or juices, as semi-solid pharmaceutical preparations in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols.
  • suitable additives and/or auxiliary agents therefore also excipients, fillers, solvents, diluents, dyes and/or binders and may be administered as liquid pharmaceutical preparations in the form of injection solutions, drops or juices, as semi-solid pharmaceutical preparations in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols.
  • auxiliary agents etc.
  • compositions depend on whether the pharmaceutical composition is to be applied orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example to the skin, the mucous membranes or into the eyes.
  • Preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral application, solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative applications.
  • 3-pyrrolidine-indole derivatives according to the invention in a deposit, in dissolved form or in a plaster, optionally with the addition of agents promoting skin penetration are suitable percutaneous application preparations.
  • Orally or percutaneously administrable preparation forms can release the 3-pyrrolidine-indole derivatives according to the invention after a delay.
  • other active ingredients known to the person skilled in the art may be added to the pharmaceutical compositions according to the invention.
  • the amount of active ingredient to be administered to the patient varies as a function of the weight of the patient, the type of application, the indication and the severity of the illness. Conventionally, 0.005 to 1,000 mg/kg, preferably 0.05 to 5 mg/kg of at least one 3-pyrrolidine-indole derivative according to the invention are applied.
  • a 3-pyrrolidine-indole derivative is contained as a pure diastereomer and/or enantiomer, as a racemate or as a non-equimolar or equimolar blend of the diastereomers and/or enantiomers.
  • the invention also relates to the use of a 3-pyrrolidine-indole derivative according to the invention for producing a pharmaceutical composition for treating pain, in particular acute, neuropathic or chronic pain.
  • the invention also relates to the use of a 3-pyrrolidine-indole derivative according to the invention for producing a pharmaceutical composition for treating depression and/or for anxiolysis.
  • the substituted 3-pyrrolidine-indole derivative of general formula I is suitable for treating cardiovascular diseases, urinary incontinence diarrhea, pruritus, alcohol and drug abuse, medicine or substance dependency, inflammations, lethargy, bulimia, anorexia, catalepsy, for use as a local anaesthetic, an anti-arrhythmic, an anti-emetic, a nootropic, and for increasing alertness and libido.
  • the invention therefore relates to the use of a substituted 3-pyrrolidine-indole derivative of general formula I for producing a pharmaceutical composition for treating cardiovascular diseases, urinary incontinence diarrhea, pruritus, alcohol and drug abuse, medicine dependency, inflammations, lethargy, bulimia, anorexia, catalepsy, for use as a local anaesthetic, an anti-arrhythmic, an anti-emetic, a nootropic, and for increasing alertness and libido.
  • the substituted 3-pyrrolidine-indole derivatives according to the invention used for producing a pharmaceutical composition for treating pain, in particular acute, neuropathic or chronic pain, depression and/or for anxiolysis, for treating cardiovascular diseases, urinary incontinence, diarrhea, pruritus, alcohol and drug abuse, substance dependency, inflammations, lethargy, bulimia, anorexia, catalepsy, for use as a local anaesthetic, an anti-arrhythmic, an anti-emetic, a nootropic, and for increasing alertness and libido are particularly preferably selected from the following group:
  • the invention also relates to a method for producing a 3-pyrrolidine-indole derivative according to the invention.
  • 3-pyrrolidine-indole derivatives of general formula I are produced according to the following diagram:
  • indole (II) was reacted with maleinimide in a manner known per se by adding acetic acid and then reacted with LiAlH 4 to form 3-pyrrolidin-3-yl-indole (III).
  • the indole nitrogen was alkylated by adding an alkylation agent, preferably an alkyl halide or a benzyl halide, for example 3-fluorobenzyl bromide.
  • the pyrrolidine nitrogen was reacted with a 2-chloroacetamide or a 2-bromoacetamide, for example 2-chloro-N-(4-trifluoromethylphenyl)-acetamide, an acid chloride, for example 2-chlorobenzoyl chloride, an isocyanate, for example 1,2-dichloro-4-isocyanatomethyl-benzene, or an isothiocyanate, for example 1-isothiocyanato-3-trifluoromethyl-benzene.
  • a 2-chloroacetamide or a 2-bromoacetamide for example 2-chloro-N-(4-trifluoromethylphenyl)-acetamide
  • an acid chloride for example 2-chlorobenzoyl chloride
  • an isocyanate for example 1,2-dichloro-4-isocyanatomethyl-benzene
  • an isothiocyanate for example 1-isothiocyanato-3-trifluoromethyl-benzene
  • R 1 represented H
  • IV was reacted directly by reaction with a 2-chloroacetamide or a 2-bromoacetamide, for example 2-chloro-N-(4-trifluoromethylphenyl)-acetamide, an acid chloride, for example 2-chlorobenzoylchloride, an isocyanate, for example 1,2-dichloro-4-isocyanatomethyl-benzene, or an isothiocyanate, for example 1-isothiocyanato-3-trifluoromethyl-benzene, to form compounds of general formula I.
  • a 2-chloroacetamide or a 2-bromoacetamide for example 2-chloro-N-(4-trifluoromethylphenyl)-acetamide
  • an acid chloride for example 2-chlorobenzoylchloride
  • an isocyanate for example 1,2-dichloro-4-isocyanatomethyl-benzene
  • an isothiocyanate for example 1-isothio
  • Compounds Compound R 1 R 2 Name 1 4-trifluoromethyl 4-propyl-benzoyl (4-propyl-phenyl)- ⁇ 3-[1-(4-trifluoromethyl-benzyl)-1H- benzyl indol-3-yl]-pyrrolidin-1-yl ⁇ -methanone 2 3-methylbutyl 3,4-dimethoxy-benzoyl (3,4-dimethoxy-phenyl)- ⁇ 3-[1-(3-methyl-butyl)-1H-indol- 3-yl]-pyrrolidin-1-yl ⁇ -methanone 3 butyl 2-methyl-6- [3-(1-(butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-methyl-6- trifluoromethyl- trifluoromethyl-pyridin-3-yl)-methanone nicotinoyl 4 3-methoxy-benzyl 3-phenyl-acryloy
  • the binding site 2 of the sodium channel is what is known as the batrachotoxin (BTX) binding site.
  • BTX batrachotoxin
  • [ 3 H]-batrachotoxinin A20 ⁇ -benzoate (10 nM in a batch) was used as the ligand.
  • These ion channel particles were enriched from rat cerebrocortex according to Gray and Whittaker (E. G. Gray and V. P. Whittaker (1962) J. Anat. 76, 79-88).
  • the radioactivity measured in the presence of veratridine (0.3 mM in a batch) is defined as the unspecific bond. Incubation was carried out at 25° C. for 120 min.

Abstract

Substituted 3-pyrrolidine-indole derivatives and methods for their production. Also pharmaceutical compositions containing these compounds and the use of these substances in methods of treatment, in particular treatment of pain and/or depression.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims the priority of Federal Republic of Germany Patent Application No. 103 37 184.2, filed Aug. 13, 2003, the disclosure of which is expressly incorporated by reference herein.
    • FIELD OF THE INVENTION
  • The invention relates to substituted 3-pyrrolidine-indole derivatives, to methods for their production, to pharmaceutical compositions containing these compounds and to the use of these substances for producing pharmaceutical compositions, and to related treatment methods including methods for treating pain and/or depression.
    • BACKGROUND OF THE INVENTION
  • Depression is an affectivity disorder, in which a depressive syndrome predominates, depressive being associated with a low feeling or denoting a sad disposition. The anti-depressants used for therapy are also important adjuvants for pain therapy (in Analgesics—from Chemistry and Pharmacology to Clinical Application, 265-284, Wiley VCH, 2002), in particular for chronic pain, as the prolonged stress of pain may lead to a depressive mood in the patient. This is often the case with patients suffering from pain with cancer (Berard, Int. Med. J. 1996, 3/4 257-259). As there have previously been no painkillers with a clinically relevant anti-depressive active component, the anti-depressants have to be added as a medication supplementary to the analgesic dose. As patients with chronic pain frequently require a large number of different medicines, the additional dose of the anti-depressant leads to further stressing of the organism. For this reason and to increase acceptance, an analgesically effective substance with an anti-depressive active component would be particularly advantageous.
  • The basis of the anti-depressive efficacy is the reuptake inhibition of serotonin.
  • Various derivatives from the structural class of 3-pyrrolidine-indoles are already known from the literature.
  • WO9311106 describes 5-substituted 3-pyrrolidine-indole derivatives, wherein the radical on the pyrrolidine nitrogen represents an alkyl chain or aryl.
  • WO02051837 describes 3-pyrrolidine-indole derivatives as 5-HT6 ligands, wherein the radical on the pyrrolidine nitrogen represents an alkyl chain, in which one carbon may also be replaced by oxygen or nitrogen, cycloalkyl, cycloheteroaryl, aryl or heteroaryl.
  • WO9410171 discloses 3-pyrrolidine-indole derivatives with alkyl, aryl and alkyl aryl as nitrogen substituents of the pyrrolidine as analgesically effective compounds which, however, are substituted in the 5 position.
  • U.S. Pat. No. 3,109,844 discloses 3-pyrrolidine-indole derivatives which carry a substituted alkyl radical on the pyrrolidine nitrogen.
  • WO02079190 describes 3-pyrrolidine-indole derivatives which carry a specifically substituted alkyl radical (a saturated nitrogen heterocycle) on the pyrrolidine nitrogen. These 3-pyrrolidine-indole derivatives are chemokine antagonists.
  • WO02079151 describes 3-pyrrolidine-indole derivatives which have an alkyl chain on the pyrrolidine nitrogen, which may be interrupted by a cyclic radical, these derivatives being chemokine antagonists.
  • WO0214317 discloses 3-pyrrolidine-indole derivatives, wherein a pyrazole radical is linked via an alkyl chain, which chain may also contain heteroatoms, to the pyrrolidine nitrogen.
  • WO0143740 discloses 3-pyrrolidine-indole derivatives, wherein an aryl radical is linked via an alkyl chain, which is interrupted by a heteroatom, to the pyrrolidine nitrogen.
  • WO9958525 and WO9910346 disclose 3-pyrrolidine-indole derivatives, wherein a dihydroindole radical or 3,4-dihydro-1H-benzo[1,2,6]thiadiazine-2,2-dioxide is linked via an alkyl chain to the pyrrolidine nitrogen.
  • U.S. Pat. No. 5,891,875 describes 3-pyrrolidine-indole derivatives, wherein a substituted morpholine radical is linked via a methylcarbonyl group to the pyrrolidine nitrogen.
  • U.S. Pat. No. 5,792,760 discloses 3-pyrrolidine-indole derivatives, wherein a N-benzyl-N-(3-1H-indol-3-yl-propionyl)-acetamide radical is linked via an ethylamine group to the pyrrolidine nitrogen.
  • WO9740038 discloses compounds, wherein the pyrrolidine nitrogen is linked to an alkyl chain or a cycloalkyl ring, a phenyl radical or a nitrogen substituent via an alkylamine chain, an alkylamide chain or an amide function.
  • The majority of compounds listed are described as serotonin receptor ligands or serotonin reuptake inhibitors.
    • SUMMARY OF THE INVENTION
  • One object of the invention was to make available a new structural class of anti-depressant substances which are also capable, in particular, of treating pain.
  • It has surprisingly now been found that substituted 3-pyrrolidine-indole derivatives of general formula I, which in addition to serotonin reuptake inhibition also exhibit noradrenalin reuptake inhibition and a sodium channel bond (BTX binding site), and have a pronounced anti-depressive and also analgesic effect.
  • Certain embodiments of the invention therefore relate to substituted 3-pyrrolidine-indole derivatives of general formula I
    Figure US20050096376A1-20050505-C00001
    wherein
      • the radical R1 represents H; respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-8-alkyl; or respectively singly or multiply substituted or unsubstituted aryl bound via C1-3-alkyl, C3-8-cycloalkyl or heteroaryl; CH2CONR3R4;
      • the radical R2 represents COR5; SO2R6; CSNHR7; CONHR8 or CH2CONHR9;
      • the radicals R3 and R4 independently of one another represent respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-8-alkyl;
      • or
      • the radicals R3 and R4 together represent CH2CH2OCH2CH2, or (CH2)3-6;
      • the radical R5 represents branched or unbranched, saturated or unsaturated, substituted or unsubstituted C1-8-alkyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; respectively saturated or unsaturated, substituted or unsubstituted cycloalkyl or heterocyclyl;
      • or
        Figure US20050096376A1-20050505-C00002
        where n=1, 2, 3; m=0, 1; X═O or NH and
        Figure US20050096376A1-20050505-C00003
        has the meaning of a single bond or a double bond;
      • the radical R6 represents respectively substituted or unsubstituted aryl, respectively substituted or unsubstituted heteroaryl, respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-8-alkyl; substituted or unsubstituted, saturated or unsaturated C3-8-cycloalkyl; or respectively singly or multiply substituted or unsubstituted aryl bound via C1-3-alkyl, C3-8-cycloalkyl or heteroaryl;
      • the radical R7 represents respectively substituted or unsubstituted aryl, respectively substituted or unsubstituted heteroaryl, respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-8-alkyl; substituted or unsubstituted, saturated or unsaturated C3-8 cycloalkyl; or respectively singly or multiply substituted or unsubstituted aryl bound via C1-3-alkyl, C3-8-cycloalkyl or heteroaryl;
      • the radical R8 represents branched or unbranched, substituted or unsubstituted, saturated or unsaturated C1-8-alkyl; substituted or unsubstituted, saturated or unsaturated C3-8-cycloalkyl; respectively singly or multiply substituted or unsubstituted trifluoromethyl- or nitrosubstituted phenyl, pyrrolyl, indolyl, furyl, benzofuranyl, thienyl (thiophenyl), benzothienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, chromenyl, oxadiazolyl, isoxazoyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, or phenothiazinyl; or respectively singly or multiply substituted or unsubstituted aryl bound via C1-3-alkyl, C3-8-cycloalkyl or heteroaryl;
      • the radical R9 represents branched or unbranched, substituted or unsubstituted, saturated or unsaturated C1-8-alkyl; substituted or unsubstituted, saturated or unsaturated C3-8-cycloalkyl; trifluoromethyl- or nitrosubstituted phenyl; respectively singly or multiply substituted or unsubstituted pyrrolyl, indolyl, furyl, benzofuranyl, thienyl, benzothienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, chromenyl, oxadiazolyl, isoxazoyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, or phenothiazinyl; or respectively singly or multiply substituted or unsubstituted aryl bound via C1-3-alkyl, C3-8-cycloalkyl or heteroaryl;
      • R10 represents H; branched or unbranched, substituted or unsubstituted, saturated or unsaturated C1-8-alkyl; respectively substituted or unsubstituted aryl or heteroaryl, respectively substituted or unsubstituted benzyl or phenethyl;
      • R11 represents H; branched or unbranched, substituted or unsubstituted, saturated or unsaturated C1-8-alkyl; respectively substituted or unsubstituted aryl or heteroaryl, or respectively singly or multiply substituted or unsubstituted aryl bound via C1-3-alkyl, C3-8-cycloalkyl or heteroaryl;
      • in the form of the racemate; the enantiomers, diastereomers, blends of the enantiomers or diastereomers or of an individual enantiomer or diastereomer; the bases and/or salts of physiologically acceptable acids or cations.
  • Preferred are substituted 3-pyrrolidine-indole derivatives, wherein the radical R1 represents H; respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-8-alkyl; respectively singly or multiply substituted or unsubstituted benzyl or methylnaphthyl, particularly preferred being benzyl which is unsubstituted or singly or multiply substituted by CF3, Br, F, CN, OCH3 or CH3; CH2CONR3R4 and the remaining radicals have the meaning given above are preferred.
  • Substituted 3-pyrrolidine-indole derivatives, wherein the radical R2 represents COR5 and R5 represents 4-propylphenyl, 3,4-dimethoxyphenyl, 2-methyl-4-trifluoromethylphenyl-3-pyridine, ethenylphenyl, 2,3-difluorophenyl, 4-tert.-butylphenyl, 2-ethoxylphenyl, 3-fluoro-4-trifluoromethylphenyl, 2,3-dimethylphenyl, phenoxyethyl, phenoxymethyl, 3,4-dichlorophenyl, 4-trifluoromethylsulphanylphenyl, 2,5-dimethoxyphenyl, 2-chloro-4-nitrophenyl, 2-chlorophenyl, 4-methyl-N-phenethyl-benzylsulphonamide, 2-chloro-5-fluoro-3-methylphenyl, 3-(2-chlorophenyl)-5-methyl-isoxazole, 5-tert.-butyl-2-methylfuran, benzo[1,2,5]oxadiazole, phenylpropyl, 2-methylsulphanyl-3-pyridine, 2-chloro-5 trifluoromethylphenyl, methoxymethyl, 4-methylphenyl, biphenyl, 4-chlorobenzyl, 2,3,4,5,6-pentafluorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl, 2,6-difluoro-3-methylphenyl, 2-methylphenyl, 4-fluorophenyl, 6-chlorochromene, 2-chloro-6-fluorophenyl, ethyl cyclopentyl, 1-(4-chlorophenyl)-5-trifluoromethylpyrazole, 2,4dichlorophenyl, 2,3-dimethylphenyl, 3-nitro-4-methylphenyl, 4-bromo-3-methylphenyl, (4-chlorophenoxy)methyl, 4-chlorophenyl, 5-methylisoxazole, 3-methoxyphenyl, 2-chlorophenylethenyl, 2-chloro-4-fluoro-3-methylphenyl, 2-fluorophenyl, 3-difluoromethylsulphanylphenyl, 2-fluoro-3-chlorophenyl, cyclopropylphenyl, 1-phenyl-5propylpyrazole, 2,6-difluorophenyl, benzo[1,3]-dioxole, 4-bromophenyl, 3-chlorothiophenyl, 2-, 3- or 4-pyridine, phenyl or 3,4-difluorophenyl and the remaining radicals have the meaning given above are also preferred.
  • Substituted 3-pyrrolidine-indole derivates, wherein the radical R2 represents SO2R6 and R6 represents 2,4,6-dimethylphenyl, 4-nitrophenyl, benzyl, 4-propylphenyl, 4-chlorophenyl, 2-trifluoromethylphenyl, 2,4-difluorophenyl or 3-trifluoromethylphenyl and the remaining radicals have the meaning given above are also preferred.
  • Substituted 3-pyrrolidine-indole derivatives, wherein the radical R2 represents CSNHR7 and the radical R7represents 3-trifluoromethylphenyl and the remaining radicals have the meaning given above are also preferred.
  • Substituted 3-pyrrolidine-indole derivatives, wherein the radical R2 represents CONHR8 and the radical R8 represents 3,4-dichlorobenzyl and the remaining radicals have the meaning given above are also preferred.
  • Furthermore, substituted 3-pyrrolidine-indole derivates, wherein the radical R2 represents CH2COR9 and R9 represents 2,5-dimethylpyrazole, 3-cyano-4-methylthiophene, 4-trifluoromethylphenyl, 4-phenyl-5-trifluoromethylthiophene and the remaining radicals have the meaning given above are also preferred.
  • Particularly preferred are substituted 3-pyrrolidine-indole derivates selected from the group comprising
      • (4-propyl-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • (3,4-dimethoxy-phenyl)-{3-[1-(3-methyl-butyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • [3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-methanone
      • 1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-3-phenyl-propenone
      • (2,3-difluoro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • (4-tert-butyl-phenyl)-{3-[1-(3-methyl-butyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • {3-[1-(4-bromo-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-(4-propyl-phenyl)-methanone
      • (2-ethoxy-phenyl)-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • [3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(3-fluoro-4-trifluoromethyl-phenyl)-methanone
      • (2,3-dimethyl-phenyl)-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • 1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-2-phenoxy-propan-1-one
      • 2-(3-chloro-phenoxy)-1-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-ethanone
      • 4-{3-[1-(2-phenoxy-propionyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • N,N-dimethyl-2-{3-[1-(2,4,6-trimethyl-benzenesulphonyl)-pyrrolidin-3-yl]-indol-1-yl}-acetamide
      • (3,4-dichloro-phenyl)-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • N,N-dimethyl-2-{3-[1-(3-trifluoromethyl-phenylthiocarbamoyl)-pyrrolidin-3-yl]-indol-1-yl}-acetamide
      • 3-(1-dimethylcarbanmoylmethyl-1H-indol-3-yl)-pyrrolidin-1-carboxylic acid 3,4-dichloro-benzylamide
      • [3-(1H-indol-3-yl)-pyrrolidin-1-yl]-(4-trifluoromethylsulphanyl-phenyl)-methanone
      • 2-(3-{1-[2-(2,5-dimethoxy-phenyl)-acetyl]-pyrrolidin-3-yl}-indol-1-yl)-N,N-dimethyl-acetamide
      • (2-chloro-4-nitro-phenyl)-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • N,N-dimethyl-2-{3-[1-(pyridin-2-carbonyl)-pyrrolidin-3-yl]-indol-1-yl}-acetamide
      • cyclobutyl-[3-(1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • N,N-diethyl-2-[3-(1-pentanoyl-pyrrolidin-3-yl)-indol-1-yl]-acetamide
      • 3-[1-(4-nitrobenzenesulphonyl)-pyrrolidin-3-yl]-1H-indole
      • 2-[3-(1-cyclopentanecarbonyl-pyrrolidin-3-yl)-indol-1-yl]-N,N-diethyl-acetamide
      • 1-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3-phenyl-propenone
      • (2-chloro-phenyl)-[3-(1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • [3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-pyridin-3-yl-methanone
      • N,N-dimethyl-2-(3-{1-[3-phenyl-2-(toluene-4-sulphonylamino)-propionyl]-pyrrolidin-3-yl}-indol-1-yl)-acetamide
      • N,N-dimethyl-2-[3-(1-phenylmethanesulphonyl-pyrrolidin-3-yl)-indol-1-yl]-acetamide
      • 4-{3-[1-(2-chloro-6-fluoro-3-methyl-benzoyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • [3-(2-chloro-phenyl)-5-methyl-isoxazol-4-yl]-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1yl]-methanone
      • 2-{3-[1-(5-tert-butyl-2-methyl-furan-3-carbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 4-{3-[1-(benzo[1,2,5]oxadiazole-5-carbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 1-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3-phenyl-propan-1-one
      • 1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-3-phenyl-propan-1-one
      • [3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-methylsulphanyl-pyridin-3-yl)-methanone
      • (2-chloro-5-trifluoromethyl-phenyl)-[3-(1-ethyl-i H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • (2-chloro-4-nitro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1 yl}-methanone
      • (2-chloro-pyridin-3-yl)-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • 2-methoxy-1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-ethanone
      • {3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-(2-methyl-6-trifluoromethylpyridin-3-yl)-methanone
      • {3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-p-tolyl-methanone
      • (2-methylsulphanyl-pyridin-3-yl)-[3-(1-prop-2-ynyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • biphenyl-4-yl-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • 2-(4-chloro-phenyl)-1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-ethanone
      • [3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-pentafluorophenyl-methanone
      • [3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-trifluoromethyl-phenyl)-methanone
      • 2-[3-(1-but-2-ynyl-1H-indol-3-yl)-pyrrolidin-1-yl]-N-(2,5-dimethyl-2H-pyrazol-3-yl)-acetamide
      • N-(3-cyano-4-methyl-thiophen-2-yl)-2-{3-[1-(3,5-dimethyl-benzyl)-1H-indol-3-yl]pyrrolidin-1-yl}-acetamide
      • N,N-diethyl-2-(3-{1-[(4-trifluoromethyl-phenyl carbamoyl)-methyl]-pyrrolidin-3-yl}-indol-1-yl)-acetamide
      • N-(3-cyano-4-methyl-thiophen-2-yl)-2-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-acetamide
      • 2-{3-[1-(3,4-difluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-N-(4-phenyl-5-trifluoromethyl-thiophen-3-yl)-acetamide
      • N,N-dimethyl-2-{3-[1-(4-propyl-benzenesulphonyl)-pyrrolidin-3-yl]-indol-1-yl}-acetamide
      • (2-chloro-4-nitro-phenyl)-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • 3-{3-[1-(4-chloro-benzenesulphonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-3,3-dimethyl-butan-1-one
      • 2-(4-chloro-phenyl)-1-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-ethanone
      • (2,6-difluoro-3-methyl-phenyl)-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • [3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-o-tolyl-methanone
      • [3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-fluoro-phenyl)-methanone
      • [3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(6-chloro-2H-chromen-3-yl)-methanone
      • (2-chloro-6-fluoro-phenyl)-[3-(1-naphthalen-2-ylmethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • 2-{3-[1-(3-cyclopentyl-propionyl)-pyrrolidin-3-yl]-indol-1-yl}-N,N-dimethyl-acetamide
      • [3-(2-chloro-phenyl)-5-methyl-isoxazol-4-yl]-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • [1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • [3-(1-allyl-1H-indol-3-yl)-pyrrolidin-1-yl]-p-tolyl-methanone
      • {3-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-pyridin-2-yl-methanone
      • (3,4-dichloro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • 1-butyl-3-[1-(2,5-dimethoxy-benzenesulphonyl)-pyrrolidin-3-yl]-1H-indole
      • 1-[3-(1-allyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3,3-dimethyl-butan-1-one
      • 4-{3-[1-(2-methoxy-acetyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • (2,4-difluoro-phenyl)-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • (2,3-dimethyl-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • [3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-methyl-3-nitro-phenyl)-methanone
      • (4-bromo-3-methyl-phenyl)-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • 1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-(4-chloro-phenoxy)-ethanone
      • 2-(4-chloro-phenyl)-1-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-ethanone
      • (4-chloro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • [3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(5-methyl-isoxazol-3-yl )-methanone
      • 1-[3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-(4-chloro-phenoxy)-ethanone
      • [3-(1-naphthalen-2-ylmethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-trifluoromethylphenyl)-methanone
      • (3-methoxy-phenyl)-(3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • 1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3-(2-chloro-phenyl)-propenone
      • 1-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-phenyl-butane-1-one
      • (2-chloro-6-fluoro-3-methyl-phenyl)-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • 2-{3-[1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-indol-1-yl}-N,N-dimethyl-acetamide
      • 2-{3-[1-(2-fluoro-benzoyl)-pyrrolidin-3-yl]-indol-1-yl}-N,N-dimethyl-acetamide
      • (3-difluoromethylsulphanyl-phenyl)-[3-(1-naphthalen-2-ylmethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • benzo[1,2,5]oxadiazol-5-yl-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • o-tolyl-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • N,N-dimethyl-2-{3-[1-(2-trifluoromethyl-benzenesulphonyl)-pyrrolidin-3-yl]-indol-1-yl}-acetamide
      • 1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-phenoxy-propan-1-one
      • (6-chloro-2-fluoro-3-methyl-phenyl)-[3-(1-naphthalen-2-ylmethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • [3-(1-allyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-methanone
      • [3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-propyl-phenyl)-methanone
      • 2-{3-[1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-indol-1-yl)-N,N-dimethyl-acetamide
      • 1-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-3-phenyl-propan-1-one
      • {3-[1-(2-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-(1-phenyl-5-propyl-1H-pyrazol-4-yl)-methanone
      • 3-{3-[1-(5-tert-butyl-2-methyl-furan-3-carbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 3-[1-(2,4-difluoro-benzenesulphonyl)-pyrrolidin-3-yl]-1-(2-fluoro-benzyl)-1H-indole
      • 2-{3-[1-(2,6-difluoro-benzoyl)-pyrrolidin-3-yl]-indol-1-yl}-N,N-dimethyl-acetamide
      • 1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-butane-1-one
      • 4-{3-[1-(2-propyl-pentanoyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 2-(4-chloro-phenoxy)-1-[3-(1-prop-2-ynyl-1H-indol-3-yl)-pyrrolidin-1-yl]-ethanone
      • [3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-pyridin-3-yl-methanone
      • 3-{3-[1-(benzo[1,3]dioxole-5-carbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • [3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-chloro-5-trifluoromethyl-phenyl)-methanone
      • (3-chloro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • 2-{3-[1-(4-bromo-benzoyl)-pyrrolidin-3-yl]-indol-1-yl}-N,N-dimethyl-acetamide
      • 3-phenyl-1-[3-(1-prop-2-ynyl-1H-indol-3-yl)-pyrrolidin-1-yl]-propenone
      • 3-{3-[1-(3-chloro-2-fluoro-benzoyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 3-{3-[1-(2-phenyl-cyclopropanecarbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 3-{3-[1-(3-chloro-thiophene-2-carbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 1-prop-2-ynyl-3-[1-(2-trifluoromethyl-benzenesulphonyl)-pyrrolidin-3-yl]-1H-indole
      • 1-(2-fluoro-benzyl)-3-[1-(3-trifluoromethyl-benzenesulphonyl)-pyrrolidin-3-yl]-1H-indole
      • [3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(6-chloro-2H-chromen-3-yl)-methanone
      • [3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(3,4-difluoro-phenyl)-methanone
        in the form of the racemate; the enantiomers, diastereomers, blends of the enantiomers or diastereomers or of an individual enantiomer or diastereomer; the bases and/or salts of physiologically acceptable acids or cations.
  • According to this invention the expressions “C1-8 alkyl” and “C1-3 alkyl” include acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight-chained and unsubstituted or singly or multiply substituted, by 1 to 8 or 1 to 3 carbon atoms, i.e. C1-8 alkanyls, C2-8 alkenyls and C2-8 alkinyls or C1-3 alkanyls, C2-3 alkenyls and alkinyls. Alkenyls have at least one C—C double bond and alkinyls at least one C—C triple bond. Alkyl is advantageously selected from the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, 2-hexyl, n-heptyl, n-octyl, 1,1,3,3-tetramethylbutyl; ethylenyl (vinyl), ethinyl, propenyl (—CH2CH═CH2, —CH═CH—CH3, —C(═CH2)—CH3), propinyl (—CH—C≡CH), butenyl, butinyl, pentenyl, pentinyl, hexenyl, hexinyl, heptenyl, heptinyl, octenyl and octinyl.
  • The expression “C3-8 cycloalkyl” represents for the purposes of this invention, cyclic hydrocarbons with 3 to 8 carbon atoms, which may be saturated or unsaturated, unsubstituted or singly or multiply substituted. C3-8 cycloalkyl is advantageously selected from the group comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl und cyclooctenyl. Cycloalkyl particularly preferably represents cyclohexyl, cyclopentyl and cyclobutyl.
  • The expression “heterocyclyl” represents a 3-, 4-, 5-, 6- or 7-membered cyclic organic radical containing at least 1, possibly also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms may be the same or different and the cyclic radical may be saturated or unsaturated, but is not aromatic, and may be unsubstituted or singly or multiply substituted. The heterocycle may also be part of a bicyclic or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulphur. It is preferred if the heterocyclyl radical is selected from the group comprising tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein the bond with the compound of general structure I may be made by any ring member of the heterocyclyl radical.
  • According to this invention the expression “aryl” represents aromatic hydrocarbons, inter alia phenyls, naphthyls and phenanthracenyls. The aryl radicals may also be condensed with further saturated, (partially) unsaturated or aromatic ring systems. Each aryl radical may be present in an unsubstituted or singly or multiply substituted form, wherein the aryl substituents may be the same or different and in any arbitrary and possible position of the aryl. Aryl is advantageously selected from the group comprising phenyl, 1-naphthyl and 2-naphthyl which may each be unsubstituted or singly or multiply substituted.
  • The expression “heteroaryl” represents a 5-, 6- or 7-membered cyclic aromatic radical which contains at least 1, possibly also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms may be the same or different and the heterocycle may be unsubstituted or singly or multiply substituted; in the case of substitution on the heterocycle the heteroaryl substituents may be the same or different and in any position of the heteroaryl. The heterocycle may also be part of a bicyclic or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulphur. It is preferred if the heteroaryl radical is selected from the group comprising pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, pyrazolyl, imidazolyl, chromenyl, oxadiazolyl, thiazolyl, oxazolyl, isoxazoyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indolyl, indazolyl, purinyl, pyrimidinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, wherein the bond with the compounds of general structure I may be made by any arbitrary and possible ring member of the heteroaryl radical. For the purposes of this invention pyridin-2-yl, pyridin-3-yl, furan-2-yl, furan-3-yl, thien-2-yl (2-thiophene), thien-3-yl (3-thiophene), isoxazol-4-yl, isoxazol-3-yl, pyrazol-3-yl, pyrazol-4-yl, chromen-3-yl and oxadiazol-3-yl, which may each be unsubstituted or singly or multiply substituted, are particularly preferred heteroaryl radicals.
  • For the purposes of the present invention the expression “aryl bound via C1-3-alkyl, C3-8-cycloalkyl or heteroaryl” means that C1-3 alkyl and C3-8-cycloalkyl, aryl and heteroaryl have the meanings defined above and the cycloalkyl, aryl or heteroaryl radical is bound by a C1-3 alkyl group to the compound of general structure I.
  • In conjunction with “alkyl”, “alkanyl”, “alkenyl” and “alkinyl”, the term “substituted” is taken to mean, according to this invention, the substitution of a hydrogen radical by F, Cl, Br, I, —CN, —N≡C, NH2, NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-heterocyclyl, NH-alkyl-OH, N(alkyl)2, N(alkyl-aryl)2, N(alkyl-heteroaryl)2, N(heterocyclyl)2, N(alkyl-OH)2, NO, NO2, SH, S-alkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-heterocyclyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, O-heterocyclyl, O-alkyl-OH, CHO, C(═O)C1-6-alkyl, C(═S)C1-6-alkyl, C(═O)aryl, C(═S)aryl, C(═O)C1-6-alkyl-aryl, C(═S)C1-6-alkyl-aryl, C(═O)-heteroaryl, C(═S)-heteroaryl, C(═O)-heterocyclyl, C(═S)-heterocyclyl, CO2H, CO2-alkyl, CO2-alkyl-aryl, C(═O)NH2, C(═O)NH-alkyl, C(═O)NH-aryl, C(═O)NH-heterocyclyl, C(═O)N(alkyl)2, C(═O)N(alkyl-aryl)2, C(═O)N(alkyl-heteroaryl)2, C(═O)N(heterocyclyl)2, SO-alkyl, SO2-alkyl, SO2NH2, SO3H, PO(O—C1-6-alkyl)2, Si(C1-6-alkyl)3, Si(C3-8-cycloalkyl)3, Si(CH2-C3-8-cycloalkyl)3, Si(phenyl)3, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein multiply substituted radicals are taken to mean those radicals which are substituted either on different atoms or multiply, for example twice or three times, on the same atoms, for example three times on the same carbon atom as in the case of CF3 or —CH2CF3 or at different positions as in the case of —CH(OH)—CH═CH—CHCl2. Multiple substitution may be made with the same or with different substituents. A substituent may also, in turn, be substituted; therefore O-alkyl also comprises inter alia —O—CH2—CH2—O—CH2—CH2—OH. For the purposes of the present invention “alkyl” particularly preferably represents methyl, ethyl, propyl, —OCH3 or —CN.
  • With respect to “aryl”, “heterocyclyl”, “heteroaryl” “cycloalkyl”, according to this invention “singly or multiply substituted” is taken to mean the single or multiple, for example double, triple or fourfold, substitution of one or more hydrogen atoms of the ring system by F, Cl, Br, I, CN, NH2, NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-heterocyclyl, NH-alkyl-OH, N(alkyl)2, N(alkyl-aryl)2, N(alkyl-heteroaryl)2, N(heterocyclyl)2, N(alkyl-OH)2, NO, NO2, SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-heterocyclyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, O-heterocyclyl, O-alkyl-OH, CHO, C(═O)C1-6-alkyl, C(═S)C1-6-alkyl, C(═O)aryl, C(═S)aryl, C(═O)—C1-6-alkyl-aryl, C(═S)C1-6-alkyl-aryl, C(═O)-heteroaryl, C(═S)-heteroaryl, C(═O)-heterocyclyl, C(═S)-heterocyclyl, CO2H, CO2-alkyl, CO2-alkyl-aryl, C(═O)NH2, C(═O)NH-alkyl, C(═O)NH-aryl, C(═O)NH-heterocyclyl, C(═O)N(alkyl)2, C(═O)N(alkyl-aryl)2, C(═O)N(alkyl-heteroaryl)2, C(═O)N(heterocyclyl)2, S(O)-alkyl, S(O)-aryl, SO2-alkyl, SO2-aryl, SO2NH2, SO3H, CF3, ═O, ═S; alkyl, cycloalkyl, aryl, heteroaryl and/or heterocyclyl; on one or possibly various atoms (wherein one substituent may, in turn, possibly be substituted). The multiple substitution is made here with the same or with different substituents. Particularly preferred substituents for “aryl” are —F, —Cl, —Br, —CF3, —O—CH3, —O—CH2CH3, methyl, n-propyl, nitro, tert.-butyl, —CN, —SCF3, phenyl and —SCHF2. Particularly preferred substituents for “heteroaryl” are methyl, —CF3, phenyl, 2-chlorophenyl, 4-chlorophenyl, —SCH3, —Cl, —CN, n-propyl and tert.butyl. —Cl is a preferred substituent for “heterocyclyl”.
  • According to the invention, the term salt formed with a physiologically acceptable acid refers to salts of the respective active ingredient with inorganic or organic acids which are physiologically acceptable—in particular when applied to humans and/or mammals. Hydrochloride is particularly preferred. Examples of physiologically acceptable acids are: hydrochloric acid, hydrobromic acid, sulphuric acid, methane sulphonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydrolλ6-benzo[d]isothiazol-3-one (saccharic acid), monomethyl sebacic acid, 5-oxo-proline, hexane-l-sulphonic acid, nicotinic acid, 2-, 3- or 4-amino benzoic acid, 2,4,6-trimethyl-benzoic acid, a-lipoic acid, acetyl glycine, acetyl salicylic acid, hippuric acid and/or aspartic acid.
  • The substances according to the invention are suitable as pharmaceutical active ingredients in pharmaceutical compositions. The invention therefore also relates to pharmaceutical compositions containing at least one 3-pyrrolidine-indole derivative according to the invention and to optionally suitable additives and/or auxiliaries and/or optionally further active ingredients.
  • The pharmaceutical compositions according to the invention contain, in addition to at least one substituted 3-pyrrolidine-indole derivative according to the invention, optionally suitable additives and/or auxiliary agents, therefore also excipients, fillers, solvents, diluents, dyes and/or binders and may be administered as liquid pharmaceutical preparations in the form of injection solutions, drops or juices, as semi-solid pharmaceutical preparations in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols. The choice of auxiliary agents, etc. and the quantities thereof to be used depend on whether the pharmaceutical composition is to be applied orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example to the skin, the mucous membranes or into the eyes. Preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral application, solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative applications. 3-pyrrolidine-indole derivatives according to the invention in a deposit, in dissolved form or in a plaster, optionally with the addition of agents promoting skin penetration, are suitable percutaneous application preparations. Orally or percutaneously administrable preparation forms can release the 3-pyrrolidine-indole derivatives according to the invention after a delay. In principle, other active ingredients known to the person skilled in the art may be added to the pharmaceutical compositions according to the invention.
  • The amount of active ingredient to be administered to the patient varies as a function of the weight of the patient, the type of application, the indication and the severity of the illness. Conventionally, 0.005 to 1,000 mg/kg, preferably 0.05 to 5 mg/kg of at least one 3-pyrrolidine-indole derivative according to the invention are applied.
  • In a preferred form of the pharmaceutical composition, a 3-pyrrolidine-indole derivative is contained as a pure diastereomer and/or enantiomer, as a racemate or as a non-equimolar or equimolar blend of the diastereomers and/or enantiomers.
  • The invention also relates to the use of a 3-pyrrolidine-indole derivative according to the invention for producing a pharmaceutical composition for treating pain, in particular acute, neuropathic or chronic pain.
  • The invention also relates to the use of a 3-pyrrolidine-indole derivative according to the invention for producing a pharmaceutical composition for treating depression and/or for anxiolysis.
  • It has surprisingly been found that the substituted 3-pyrrolidine-indole derivative of general formula I is suitable for treating cardiovascular diseases, urinary incontinence diarrhea, pruritus, alcohol and drug abuse, medicine or substance dependency, inflammations, lethargy, bulimia, anorexia, catalepsy, for use as a local anaesthetic, an anti-arrhythmic, an anti-emetic, a nootropic, and for increasing alertness and libido.
  • The invention therefore relates to the use of a substituted 3-pyrrolidine-indole derivative of general formula I for producing a pharmaceutical composition for treating cardiovascular diseases, urinary incontinence diarrhea, pruritus, alcohol and drug abuse, medicine dependency, inflammations, lethargy, bulimia, anorexia, catalepsy, for use as a local anaesthetic, an anti-arrhythmic, an anti-emetic, a nootropic, and for increasing alertness and libido.
  • The substituted 3-pyrrolidine-indole derivatives according to the invention used for producing a pharmaceutical composition for treating pain, in particular acute, neuropathic or chronic pain, depression and/or for anxiolysis, for treating cardiovascular diseases, urinary incontinence, diarrhea, pruritus, alcohol and drug abuse, substance dependency, inflammations, lethargy, bulimia, anorexia, catalepsy, for use as a local anaesthetic, an anti-arrhythmic, an anti-emetic, a nootropic, and for increasing alertness and libido are particularly preferably selected from the following group:
      • (4-propyl-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • (3,4-dimethoxy-phenyl)-{3-[1-(3-methyl-butyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • [3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-methanone
      • 1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-3-phenyl-propenone
      • (2,3-difluoro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • (4-tert-butyl-phenyl)-{3-[1-(3-methyl-butyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • {3-[1-(4-bromo-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-(4-propyl-phenyl)-methanone
      • (2-ethoxy-phenyl)-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • [3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(3-fluoro-4-trifluoromethyl-phenyl)-methanone
      • (2,3-dimethyl-phenyl)-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • 1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-2-phenoxy-propan-1-one
      • 2-(3-chloro-phenoxy)-1-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-ethanone
      • 4-{3-[1-(2-phenoxy-propionyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • N,N-dimethyl-2-{3-[1-(2,4,6-trimethyl-benzenesulphonyl)-pyrrolidin-3-yl]-indol-1-yl}-acetamide
      • (3,4-dichloro-phenyl)-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • N,N-dimethyl-2-{3-[1-(3-trifluoromethyl-phenylthiocarbamoyl)-pyrrolidin-3-yl]-indol-1-yl}-acetamide
      • 3-(1-dimethylcarbanmoylmethyl-1H-indol-3-yl)-pyrrolidin-1-carboxylic acid 3,4-dichloro-benzylamide
      • [3-(1H-indol-3-yl)-pyrrolidin-1-yl]-(4-trifluoromethylsulphanyl-phenyl)-methanone
      • 2-(3-{1-[2-(2,5-dimethoxy-phenyl)-acetyl]-pyrrolidin-3-yl}-indol-1-yl)-N,N-dimethyl-acetamide
      • (2-chloro-4-nitro-phenyl)-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • N,N-dimethyl-2-{3-[1-(pyridin-2-carbonyl)-pyrrolidin-3-yl]-indol-1-yl}-acetamide
      • cyclobutyl-[3-(1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • N,N-diethyl-2-[3-(1-pentanoyl-pyrrolidin-3-yl)-indol-1-yl]-acetamide
      • 3-[1-(4-nitrobenzenesulphonyl)-pyrrolidin-3-yl]-1H-indole
      • 2-[3-(1-cyclopentanecarbonyl-pyrrolidin-3-yl)-indol-1-yl]-N,N-diethyl-acetamide
      • 1-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3-phenyl-propenone
      • (2-chloro-phenyl)-[3-(1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • [3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-pyridin-3-yl-methanone
      • N,N-dimethyl-2-(3-{1-[3-phenyl-2-(toluene-4-sulphonylamino)-propionyl]-pyrrolidin-3-yl}-indol-1-yl)-acetamide
      • N,N-dimethyl-2-[3-(1-phenylmethanesulphonyl-pyrrolidin-3-yl)-indol-1-yl]-acetamide
      • 4-{3-[1-(2-chloro-6-fluoro-3-methyl-benzoyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • [3-(2-chloro-phenyl)-5-methyl-isoxazol-4-yl]-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1yl]-methanone
      • 2-{3-[1-(5-tert-butyl-2-methyl-furan-3-carbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 4-{3-[1-(benzo[1,2,5]oxadiazole-5-carbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 1-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3-phenyl-propan-1-one
      • 1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-3-phenyl-propan-1-one
      • [3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-methylsulphanyl-pyridin-3-yl)-methanone
      • (2-chloro-5-trifluoromethyl-phenyl)-[3-(1-ethyl-i H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • (2-chloro-4-nitro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1 yl}-methanone
      • (2-chloro-pyridin-3-yl)-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • 2-methoxy-1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-ethanone
      • {3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-(2-methyl-6-trifluoromethylpyridin-3-yl)-methanone
      • {3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-p-tolyl-methanone
      • (2-methylsulphanyl-pyridin-3-yl)-[3-(1-prop-2-ynyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • biphenyl-4-yl-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • 2-(4-chloro-phenyl)-1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-ethanone
      • [3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-pentafluorophenyl-methanone
      • [3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-trifluoromethyl-phenyl)-methanone
      • 2-[3-(1-but-2-ynyl-1H-indol-3-yl)-pyrrolidin-1-yl]-N-(2,5-dimethyl-2H-pyrazol-3-yl)-acetamide
      • N-(3-cyano-4-methyl-thiophen-2-yl)-2-{3-[1-(3,5-dimethyl-benzyl)-1H-indol-3-yl]pyrrolidin-1-yl}-acetamide
      • N,N-diethyl-2-(3-{1-[(4-trifluoromethyl-phenyl carbamoyl)-methyl]-pyrrolidin-3-yl}-indol-1-yl)-acetamide
      • N-(3-cyano-4-methyl-thiophen-2-yl)-2-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-acetamide
      • 2-{3-[1-(3,4-difluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-N-(4-phenyl-5-trifluoromethyl-thiophen-3-yl)-acetamide
      • N,N-dimethyl-2-{3-[1-(4-propyl-benzenesulphonyl)-pyrrolidin-3-yl]-indol-1-yl}-acetamide
      • (2-chloro-4-nitro-phenyl)-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • 3-{3-[1-(4-chloro-benzenesulphonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-3,3-dimethyl-butan-1-one
      • 2-(4-chloro-phenyl)-1-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-ethanone
      • (2,6-difluoro-3-methyl-phenyl)-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • [3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-o-tolyl-methanone
      • [3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-fluoro-phenyl)-methanone
      • [3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(6-chloro-2H-chromen-3-yl)-methanone
      • (2-chloro-6-fluoro-phenyl)-[3-(1-naphthalen-2-ylmethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • 2-{3-[1-(3-cyclopentyl-propionyl)-pyrrolidin-3-yl]-indol-1-yl}-N,N-dimethyl-acetamide
      • [3-(2-chloro-phenyl)-5-methyl-isoxazol-4-yl]-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • [1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • [3-(1-allyl-1H-indol-3-yl)-pyrrolidin-1-yl]-p-tolyl-methanone
      • {3-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-pyridin-2-yl-methanone
      • (3,4-dichloro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • 1-butyl-3-[1-(2,5-dimethoxy-benzenesulphonyl)-pyrrolidin-3-yl]-1H-indole
      • 1-[3-(1-allyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3,3-dimethyl-butan-1-one
      • 4-{3-[1-(2-methoxy-acetyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • (2,4-difluoro-phenyl)-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • (2,3-dimethyl-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • [3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-methyl-3-nitro-phenyl)-methanone
      • (4-bromo-3-methyl-phenyl)-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • 1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-(4-chloro-phenoxy)-ethanone
      • 2-(4-chloro-phenyl)-1-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-ethanone
      • (4-chloro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • [3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(5-methyl-isoxazol-3-yl )-methanone
      • 1-[3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-(4-chloro-phenoxy)-ethanone
      • [3-(1-naphthalen-2-ylmethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-trifluoromethylphenyl)-methanone
      • (3-methoxy-phenyl)-(3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • 1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3-(2-chloro-phenyl)-propenone
      • 1-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-phenyl-butane-1-one
      • (2-chloro-6-fluoro-3-methyl-phenyl)-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • 2-{3-[1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-indol-1-yl}-N,N-dimethyl-acetamide
      • 2-{3-[1-(2-fluoro-benzoyl)-pyrrolidin-3-yl]-indol-1-yl}-N,N-dimethyl-acetamide
      • (3-difluoromethylsulphanyl-phenyl)-[3-(1-naphthalen-2-ylmethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • benzo[1,2,5]oxadiazol-5-yl-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • o-tolyl-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • N,N-dimethyl-2-{3-[1-(2-trifluoromethyl-benzenesulphonyl)-pyrrolidin-3-yl]-indol-1-yl}-acetamide
      • 1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-phenoxy-propan-1-one
      • (6-chloro-2-fluoro-3-methyl-phenyl)-[3-(1-naphthalen-2-ylmethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
      • [3-(1-allyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-methanone
      • [3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-propyl-phenyl)-methanone
      • 2-{3-[1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-indol-1-yl)-N,N-dimethyl-acetamide
      • 1-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-3-phenyl-propan-1-one
      • {3-[1-(2-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-(1-phenyl-5-propyl-1H-pyrazol-4-yl)-methanone
      • 3-{3-[1-(5-tert-butyl-2-methyl-furan-3-carbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 3-[1-(2,4-difluoro-benzenesulphonyl)-pyrrolidin-3-yl]-1-(2-fluoro-benzyl)-1H-indole
      • 2-{3-[1-(2,6-difluoro-benzoyl)-pyrrolidin-3-yl]-indol-1-yl}-N,N-dimethyl-acetamide
      • 1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-butane-1-one
      • 4-{3-[1-(2-propyl-pentanoyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 2-(4-chloro-phenoxy)-1-[3-(1-prop-2-ynyl-1H-indol-3-yl)-pyrrolidin-1-yl]-ethanone
      • [3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-pyridin-3-yl-methanone
      • 3-{3-[1-(benzo[1,3]dioxole-5-carbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • [3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-chloro-5-trifluoromethyl-phenyl)-methanone
      • (3-chloro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
      • 2-{3-[1-(4-bromo-benzoyl)-pyrrolidin-3-yl]-indol-1-yl}-N,N-dimethyl-acetamide
      • 3-phenyl-1-[3-(1-prop-2-ynyl-1H-indol-3-yl)-pyrrolidin-1-yl]-propenone
      • 3-{3-[1-(3-chloro-2-fluoro-benzoyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 3-{3-[1-(2-phenyl-cyclopropanecarbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 3-{3-[1-(3-chloro-thiophene-2-carbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
      • 1-prop-2-ynyl-3-[1-(2-trifluoromethyl-benzenesulphonyl)-pyrrolidin-3-yl]-1H-indole
      • 1-(2-fluoro-benzyl)-3-[1-(3-trifluoromethyl-benzenesulphonyl)-pyrrolidin-3-yl]-1H-indole
      • [3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(6-chloro-2H-chromen-3-yl)-methanone
      • [3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(3,4-difluoro-phenyl)-methanone
        in the form of the racemate, the pure stereoisomers, the enantiomers and diastereomers, in any mixing ratio; in the form of its acids or its bases or in the form of its salts, in particular the physiologically acceptable salts or salts of physiologically acceptable acids or cations; or in the form of its solvates, in particular the hydrates, and optionally containing suitable additives and/or auxiliaries and/or optionally further active ingredients.
  • The invention also relates to a method for producing a 3-pyrrolidine-indole derivative according to the invention.
  • 3-pyrrolidine-indole derivatives of general formula I are produced according to the following diagram:
    Figure US20050096376A1-20050505-C00004
  • Here, indole (II) was reacted with maleinimide in a manner known per se by adding acetic acid and then reacted with LiAlH4 to form 3-pyrrolidin-3-yl-indole (III). After protecting the pyrrolidine nitrogen with a protecting group known per se, preferably the Boc protecting group, the indole nitrogen was alkylated by adding an alkylation agent, preferably an alkyl halide or a benzyl halide, for example 3-fluorobenzyl bromide. After eliminating the protecting group, the pyrrolidine nitrogen was reacted with a 2-chloroacetamide or a 2-bromoacetamide, for example 2-chloro-N-(4-trifluoromethylphenyl)-acetamide, an acid chloride, for example 2-chlorobenzoyl chloride, an isocyanate, for example 1,2-dichloro-4-isocyanatomethyl-benzene, or an isothiocyanate, for example 1-isothiocyanato-3-trifluoromethyl-benzene. In the event that R1 represented H, IV was reacted directly by reaction with a 2-chloroacetamide or a 2-bromoacetamide, for example 2-chloro-N-(4-trifluoromethylphenyl)-acetamide, an acid chloride, for example 2-chlorobenzoylchloride, an isocyanate, for example 1,2-dichloro-4-isocyanatomethyl-benzene, or an isothiocyanate, for example 1-isothiocyanato-3-trifluoromethyl-benzene, to form compounds of general formula I.
    • EXAMPLES Example 1 Synthesis of (2-chloro-4-nitro-phenyl)-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}methanone (Compound 20)
  • 1st stage:
    Figure US20050096376A1-20050505-C00005
    220 ml acetic acid were added to a mixture of 29.5 g (251 mmol) indole (II) and 24.4 g (251 mmol) maleinimide. The reaction mixture was heated under reflux for 3 days under a nitrogen atmosphere. After removing the solvent, 500 ml ethyl acetate were added and the mixture was extracted twice with 250 ml aqueous NaHCO3 solution. The aqueous phase was extracted with 500 ml ethyl acetate. The purified organic phases were dried over Na2SO4. The crude product was purified via column chromatography (silica gel, ethyl acetate/hexane 1:1 followed by dichloromethane (DCM) followed by Et3N/DCM/MeOH 1:89:10). 25.7 g (48%) of III were obtained.
    2nd stage:
    Figure US20050096376A1-20050505-C00006
    100 ml dry tetrahydrofuran (THF) were dissolved in 15.7 g (414 mmol) LiAlH4. A solution of 17.7 g (82.6 mmol) of III in 250 ml dry THF was added dropwise within 30 min. The reaction mixture was heated overnight under reflux under a nitrogen atmosphere. 30 ml ethyl acetate were carefully added with ice cooling. After 1 hour 15 ml water were carefully added and, after further stirring at ambient temperature, 15 ml of an aqueous 2 N NaOH solution were added. The reaction mixture was heated under reflux and a further 50 ml water were added. After a further 2 hours the reaction mixture was cooled to ambient temperature and filtered. The residue was washed with THF. 16.3 g of IV were obtained and this was used without further purification.
    3rd stage:
    Figure US20050096376A1-20050505-C00007
  • A solution of 19.1 g (87.5 mmol) Boc2O in 100 ml DCM was added dropwise under a nitrogen atmosphere at 0° C. to a solution of 16.3 g IV in 500 ml DCM within 15 minutes. The reaction mixture was stirred for 2 hours at 0° C. and then overnight at ambient temperature. After purification via column chromatography (first silica gel, Et2O, second silica gel ethyl acetate/heptane 1:2), 4.1 g (17%) of Va were obtained.
    4th stage:
    Figure US20050096376A1-20050505-C00008
    126 mg (3.15 mmol) NaH (60% dispersion in mineral oil) were suspended in 6 ml dry THF under a nitrogen atmosphere. The suspension was cooled to 0° C. and 750 mg Va (2.62 mmol) were added. The mixture was stirred for 3 h at 0° C. and then for a further 30 min at ambient temperature. After repeated cooling to 0° C., 595 mg (3.15 mmol) 3-fluorobenzylbromide were added and the reaction mixture was stirred for 3 hours at 0° C. and then overnight at ambient temperature. Water and saturated aqueous NaCl solution were added and the reaction mixture extracted three times with DCM. The organic phases were dried over Na2SO4 and evaporated to dryness. The product (1.08 g) was used without further purification.
    5th stage:
    Figure US20050096376A1-20050505-C00009
  • Compound VIa (1.08 g) was dissolved in 5 ml DCM. After adding 5 ml trifluoroacetic acid (Tfa) the mixture was stirred overnight at ambient temperature. After removing the solvent, methanol and heptane were added. After distilling the methanol layer, ethyl acetate and aqueous saturated NaHCO3 solution were added. The organic layer was separated, dried over Na2SO4 and evaporated to dryness. Yield: 870 mg VIIa.
    6th stage:
    Figure US20050096376A1-20050505-C00010
  • Compound VIIa (0.87 g) was dissolved in 10 ml DCM. 299 mg (2.95 mmol) and 650 mg (2.95 mmol) 2-chloro-4-nitrobenzoylchloride were added and the reaction mixture was stirred overnight under a nitrogen atmosphere at ambient temperature. The solution was extracted in succession with 1 N NaOH, 1 N HCl and saturated aqueous NaHCO3 solution. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was purified via column chromatography (first silica gel, MeOH/DCM 1:99, second silica gel, ethyl acetate/hexane 1:2). Yield: 373 mg Compound 20.
  • The remaining example compounds were similarly produced.
  • Compounds:
    Compound R1 R2 Name
    1 4-trifluoromethyl 4-propyl-benzoyl (4-propyl-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-
    benzyl indol-3-yl]-pyrrolidin-1-yl}-methanone
    2 3-methylbutyl 3,4-dimethoxy-benzoyl (3,4-dimethoxy-phenyl)-{3-[1-(3-methyl-butyl)-1H-indol-
    3-yl]-pyrrolidin-1-yl}-methanone
    3 butyl 2-methyl-6- [3-(1-(butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-methyl-6-
    trifluoromethyl- trifluoromethyl-pyridin-3-yl)-methanone
    nicotinoyl
    4 3-methoxy-benzyl 3-phenyl-acryloyl 1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-
    yl}-3-phenyl-propenone
    5 4-trifluoromethyl 2,3-difluoro-benzoyl (2,3-difluoro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-
    benzyl 1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
    6 3-methylbutyl 4-trifluoro-methyl- (4-tert-butyl-phenyl)-{3-[1-(3-methyl-butyl)-1H-indol-3-
    benzoyl yl]-pyrrolidin-1-yl}-methanone
    7 4-bromobenzyl 4-propyl-benzoyl {3-[1-(4-bromo-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-
    (4-propyl-phenyl)-methanone
    8 3-methoxy-benzyl 2-ethoxy-benzoyl (2-ethoxy-phenyl)-{3-[1-(3-methoxy-benzyl)-1H-indol-3-
    yl]-pyrrolidin-1-yl}-methanone
    9 ethyl 4-trifluoromethyl-3- [3-(1-(ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(3-fluoro-4-
    fluoro-benzoyl trifluoromethyl-phenyl)-methanone
    10 ethyl 2,3-dimethyl-benzoyl (2,3-dimethyl-phenyl)-[3-(1-ethyl-1H-indol-3-yl)-
    pyrrolidin-1-yl]-methanone
    11 3-methoxy-benzyl 2-phenoxy-propionyl 1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-
    yl}-2-phenoxy-propan-1-one
    12 ethyl (3-chloro-phenoxy)- 2-(3-chloro-phenoxy)-1-[3-(1-ethyl-1H-indol-3-yl)-
    acetyl pyrrolidin-1-yl]-ethanone
    13 4-cyanobenzyl 2-phenoxy-propionyl 4-(3-[1-(2-phenoxy-propionyl)-pyrrolidin-3-yl]-indol-1-
    ylmethyl}-benzonitrile
    14 2-N,N-dimethyl- 2,4,6-trimethyl-benzyl- N,N-dimethyl-2-{3-[1-(2,4,6-trimethyl-
    acetamide sulphonyl benzenesulphonyl)-pyrrolidin-3-yl]-indol-1-yl}-
    acetamide
    15 ethyl 3,4-dichloro-benzoyl (3,4-dichloro-phenyl)-[3-(1-ethyl-1H-indol-3-yl)-
    pyrrolidin-1-yl]-methanone
    16 2-N,N-dimethyl- N-(3-trifluoro-methyl- N,N-dimethyl-2-{3-[1-(3-trifluoromethyl-
    acetamide phenyl)-thio-carbamoyl phenylthiocarbamoyl)-pyrrolidin-3-yl]-indol-1-yl}-
    acetamide
    17 2-N,N-dimethyl- 3,4-dichloro- 3-(1-dimethylcarbamoylmethyl-1H-indol-3-yl)-
    acetamide benzylamide pyrrolidine-1-carboxylic acid
    3,4-dichloro-benzylamide
    18 H 4-(trifluoro-methyl- [3-(1H-indol-3-yl)-pyrrolidin-1-yl]-(4-
    sulphanyl)-benzoyl trifluoromethylsulphanyl-phenyl)-methanone
    19 2-N,N-dimethyl- 2,5-dimethoxy- 2-(3-{1-[2-(2,5-dimethoxy-phenyl)-acetyl]-pyrrolidin-3-
    acetamide phenylacetyl yl}-indol-1-yl)-N,N-dimethyl-acetamide
    20 3-fluorobenzyl 2-chloro-4- (2-chloro-4-nitro-phenyl)-{3-[1-(3-fluoro-benzyl)-1H-
    nitrobenzoyl indol-3-yl]-pyrrolidin-1-yl}-methanone
    21 2-N,N-dimethyl- pyridin-2-carbonyl N,N-dimethyl-2-{3-[1-(pyridin-2-carbonyl)-pyrrolidin-3-
    acetamide yl]-indol-1-yl}-acetamide
    22 H cyclobutyl-carbonyl cyclobutyl-[3-(1H-indol-3-yl)-pyrrolidin-1-yl]-
    methanone
    23 2-N,N-diethyl- pentanoyl N,N-diethyl-2-[3-(1-pentanoyl-pyrrolidin-3-yl)-indol-1-
    acetamide yl]-acetamide
    24 H 4-nitro-benzyl- 3-[1-(4-nitro-benzenesulphonyl)-pyrrolidin-3-yl]-1H-
    sulphonyl indole
    25 2-N,N-diethyl- cyclopentyl-carbonyl 2-1[3-(1-cyclopentanecarbonyl-pyrrolidin-3-yl)-indol-1-
    acetamide yl]-N,N-diethyl acetamide
    26 methyl 3-phenyl-acryloyl 1-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3-phenyl-
    propenone
    27 H 2-chlorobenzoyl (2-chloro-phenyl)-[3-(1H-indol-3-yl)-pyrrolidin-1-yl]-
    methanone
    28 ethyl 3-pyridyl-carbonyl [3-(1-(ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-pyridin-3-yl-
    methanone
    29 2-N,N-dimethyl- 3-phenyl-2-(tolyl-4- N,N-dimethyl-2-(3-{1-[3-phenyl-2-(toluene-4-
    acetamide sulphonyl-amino)- sulphonylamino)-propionyl]-pyrrolidin-3-yl)-indol-1-yl)-
    propionyl acetamide
    30 2-N,N-dimethyl- benzyl-sulphonyl N,N-dimethyl-2-[3-(1-phenylmethanesulphonyl-
    acetamide pyrrolidin-3-yl)-indol-1-yl]-acetamide
    31 4-cyanobenzyl 2-chloro-6-fluoro-3- 4-{3-[1-(2-chloro-6-fluoro-3-methyl-benzoyl)-pyrrolidin-
    methyl-benzyl 3-yl]-indol-1-ylmethyl}-benzonitrile
    32 ethyl 3-(2-chloro-phenyl)-5- [3-(2-chloro-phenyl)-5-methyl-isoxazol-4-yl]-[3-(1-ethyl-
    methyl-isoxazol-4- 1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
    carbonyl
    33 2-cyanobenzyl 5-tert-butyl-2-methyl 2-{3-[1-(5-tert-butyl-2-methyl-furan-3-carbonyl)
    furan-3-carbonyl pyrrolidin-3-yl]-indol-1-ylmethyl)-benzonitrile
    34 4-cyanobenzyl benzo[1,2,5] oxadiazol- 4-{3-[1-(benzo[1,2,5]oxadiazole-5-carbonyl)-pyrrolidin-
    5-carbonyl 3-yl]-indol-1-ylmethyl}-benzonitrile
    35 ethyl 3-phenyl-propionyl 1-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3-phenyl-
    propan-1-one
    36 3-methoxy- 3-phenyl-propionyl 1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-
    benzyl yl}-3-phenyl-propan-1-one
    37 methyl 2-methyl-sulphanyl- [3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-
    nicotinoyl methylsulphanyl-pyridin-3-yl)-methanone
    38 ethyl 2-chloro-5- (2-chloro-5-trifluoromethyl-phenyl)-[3-(1-ethyl-1H-
    trifluoromethyl benzoyl indol-3-yl)-pyrrolidin-1-yl]-methanone
    39 4-trifluoromethyl 2-chloro-4- (2-chloro-4-nitro-phenyl)-{3-[1-(4-trifluoromethyl-
    benzyl nitrobenzoyl benzyl)-1H-indol-3-yl-pyrrolidin-1-yl}-methanone
    40 methyl 2-chloro-nicotinoyl (2-chloro-pyridin-3-yl)-[3-(1-methyl-1H-indol-3-yl)-
    pyrrolidin-1-yl]-methanone
    41 3-methoxy- methoxy-acetyl 2-methoxy-1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-
    benzyl pyrrolidin-1-yl}-ethanone
    42 3-fluorobenzyl 4-trifluoro-methyl-2- {3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-
    methyl-nicotinoyl (2-methyl-6-trifluoromethyl-pyridin-3-yl)-methanone
    43 3-methoxy- 4-methyl-benzoyl {3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-
    benzyl yl}-p-tolyl-methanone
    44 3-propinyl 2-methyl-sulphanyl- (2-methylsulphanyl-pyridin-3-yl)-[3-(1-prop-2-inyl-1H-
    nicotinoyl indol-3-yl)-pyrrolidin-1-yl]-methanone
    45 methyl 4-phenyl-benzoyl Biphenyl-4-yl-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-
    yl]-methanone
    46 3-methoxy- (4-chloro-phenyl)- 2-(4-chloro-phenyl)-1-{3-[1-(3-methoxy-benzyl)-1H-
    benzyl acetyl indol-3-yl]-pyrrolidin-1-yl}-ethanone
    47 methyl 2,3,4,5,6-pentafluoro- [3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-
    benzoyl pentafluorophenyl-methanone
    48 ethyl 4-trifluoro-methyl- [3-(11-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-
    benzyl trifluoromethyl-phenyl)-methanone
    49 1-(2-butinyl) N-(2,5-dimethyl-2H- 2-[3-(1-but-2-ynyl-1H-indol-3-yl)-pyrrolidin-1-yl]-N-
    pyrazol-3-yl)- (2,5-dimethyl-2H-pyrazol-3-yl)-acetamide
    acetamidyl
    50 3,5-dimethyl- N-(3-cyano-4-methyl- N-(3-cyano-4-methyl-thiophen-2-yl)-2-{3-[1-(3,5-
    benzyl thiophen-2-yl)-acetamidyl dimethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-
    yl}acetamide
    51 2-N,N-diethyl- N-(4-trifluoro-methyl- N,N-diethyl-2-(3-{1-[(4-trifluoromethyl-
    acetamide phenyl)-acetamidyl phenylcarbamoyl)-methyl]-pyrrolidin-3-yl}-indol-1-yl)-
    acetamide
    52 ethyl N-(3-cyano-4-methyl- N-(3-cyano-4-methyl-thiophen-2-yl)-2-[3-(1-ethyl-1H-
    thiophen-2-yl)-acetamidyl indol-3-yl)-pyrrolidin-1-yl]-acetamide
    53 3,4- N-(4-phenyl-5- 2-{3-[1-(3,4-difluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-
    difluorobenzyl trifluoro-methyl- 1-yl}-N-(4-phenyl-5-trifluiommethyl-thiophen-3-yl)-
    thiophen-3-yl)-acetamidyl acetamide
    54 2-N,N-dimethyl- 4-propyl-benzyl- N,N-dimethyl-2-{3-[1-(4-propyl-benzenesulphonyl)-
    acetamide sulphonyl pyrrolidin-3-yl]-indol-1-yl}-acetamide
    55 3-methoxy- 2-chloro-4- (2-chloro-4-nitro-phenyl)-{3-[1-(3-methoxy-benzyl)-1H-
    benzyl nitrobenzoyl indol-3-yl]-pyrrolidin-1-yl}-methanone
    56 3-cyanobenzyl 4-chloro-benzyl- 3-(3-[1-(4-chloro-benzenesulphonyl)-pyrrolidin-3-yl]-
    sulphonyl indol-1-yl methyl}-benzonitrile
    57 3-methoxy- 3,3-dimethyl-butyryl 1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-
    benzyl yl}-3,3-dimethyl-butan-1-one
    58 methyl (4-chloro-phenyl)- 2-(4-chloro-phenyl)-1-[3-(1-methyl-1H-indol-3-yl)-
    acetyl pyrrolidin-1-yl]-ethanone
    59 3-methoxy- 2,6-difluoro-3-methyl- (2,6-difluoro-3-methyl-phenyl)-{3-[1-(3-methoxy-
    benzyl benzoyl benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
    60 ethyl 2-methyl-benzoyl [3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-o-tolyl-
    methanone
    61 ethyl 4-fluoro-benzoyl [3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-fluoro-
    phenyl)-methanone
    62 n-butyl 6-chloro-2H-chromen- [3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(6-chloro-2H-
    3-carbonyl chromen-3-yl)-methanone
    63 naphthyl-methyl 2-chloro-6-fluoro- (2-chloro-6-fluoro-phenyl)-[3-(1-naphthalen-2-ylmethyl-
    benzoyl 1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
    64 2-N,N-dimethyl- 3-cyclopentyl- 2-{3-[1-(3-cyclopentyl-propionyl)-pyrrolidin-3-yl]-indol-
    acetamide propionyl 1-yl}-N,N-dimethyl-acetamide
    65 3-methoxy- 3-(2-chloro-phenyl)-5- [3-(2-chloro-phenyl)-5-methyl isoxazol-4-yl]-{3-[1-(3-
    benzyl methyl-isoxazol-4- methoxy benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl)
    carbonyl methanone
    66 3-fluorobenzyl 1-(4-chloro-phenyl)-5- [1-(4,-chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-
    trifluoromethyl-1H- yl]-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-
    pyrazol-4-carbonyl yl)-methanone
    67 2-propenyl 4-methyl-benzoyl [3-(1-allyl-1H-indol-3-yl)-pyrrolidin-1-yl]-p-tolyl-
    methanone
    68 4-fluorobenzyl pyridin-2-carbonyl {3-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-
    pyridin-2-yl-methanone
    69 4-trifluoromethyl 3,4-dichloro-benzoyl (3,4-dichloro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-
    benzyl 1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
    70 n-butyl 2,5-dimethoxy-benzoyl 1-butyl-3-[1-(2,5-dimethoxy-benzenesulphonyl)-
    pyrrolidin-3-yl]-1H-indole
    71 2-propenyl 3,3-dimethyl-butyryl 1-[3-(1-allyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3,3-
    dimethyl-butan-1-one
    72 4-cyano-benzyl methoxy-acetyl 4-{3-[1-(2-methoxy-acetyl)-pyrrolidin-3-yl]-indol-1-
    ylmethyl}-benzonitrile
    73 ethyl 2,4-difluoro-benzoyl (2,4-difluoro-phenyl)-[3-(1-ethyl-1H-indol-3-yl)-
    pyrrolidin-1-yl]-methanone
    74 4-trifluoromethyl 2,3-dimethyl-benzoyl (2,3-dimethyl-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-
    benzyl 1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
    75 n-butyl 3-nitro-4-methyl- [3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-methyl-3-
    benzoyl nitro-phenyl)-methanone
    76 3-methoxy- 4-bromo-3-methyl- (4-bromo-3-methyl-phenyl)-{3-[1-(3-methoxy-benzyl)-
    benzyl benzoyl 1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
    77 n-butyl (4-chloro-phenoxy)- 1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-(4-
    acetyl chloro-phenoxy)-ethanone
    78 3-fluorobenzyl (4-chloro-phenyl)- 2-(4-chloro-phenyl)-1-{3-[1-(3-fluoro-benzyl)-1H-indol-
    acetyl 3-yl]-pyrrolidin-1-yl}-ethanone
    79 4-trifluoromethyl 4-chloro-benzoyl (4-chloro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-
    benzyl indol-3-yl]-pyrrolidin-1-yl}-methanone
    80 benzyl 5-methyl-isoxazol-3- [3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(5-methyl-
    carbonyl isoxazol-3-yl)-methanone
    81 benzyl (4-chloro-phenoxy)- 1-[3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-(4-
    acetyl chloro-phenoxy)-ethanone
    82 methyl-naphthyl 4-trifluoro-methyl- [3-(1-naphthalen-2-ylmethyl-1H-indol-3-yl)-pyrrolidin-1-
    benzoyl yl]-(4-trifluoromethyl-phenyl)-methanone
    83 4-trifluoromethyl 3-methoxy-benzoyl (3-methoxy-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-
    benzyl 1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
    84 n-butyl 3-(2-chloro-phenyl)- 1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3-(2-
    acryloyl chloro-phenyl)-propenone
    85 methyl 2-phenyl-butyryl 1-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-phenyl-
    butan-1-one
    86 methyl 2-chloro-6-fluoro-3- (2-chloro-6-fluoro-3-methyl-phenyl)-[3-(1-methyl-1H-
    methyl-benzoyl indol-3-yl)-pyrrolidin-1-yl]-methanone
    87 2-N,N-dimethyl- 3-methoxy-benzoyl 2-{3-[1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-indol-1-
    acetamide yl}-N,N-dimethyl-acetamide
    88 2-N,N-dimethyl- 2-fluoro-benzoyl 2-{3-[1-(2-fluoro-benzoyl)-pyrrolidin-3-yl]-indol-1-yl}-
    acetamide N,N-dimethyl-acetamide
    89 methyl-naphthyl 3-difluoro-methyl- (3-difluoromethylsulphanyl-phenyl)-[3-(1-naphthalen-2-
    sulphanyl-benzoyl ylmethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
    90 3-fluorobenzyl benzo[1,2,5] oxadiazol- benzo[1,2,5]oxadiazol-5-yl-{3-[1-(3-fluoro-benzyl)-1H-
    5-carbonyl indol-3-yl]-pyrrolidin-1-yl}-methanone
    91 4- 2-methyl-benzoyl o-tolyl-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-
    trifluoromethyl- pyrrolidin-1-yl)-methanone
    benzyl
    92 2-N,N-dimethyl- 2-trifluoromethyl- N,N-dimethyl-2-{3-[1-(2-trifluoromethyl-
    acetamide benzyl-sulphonyl benzenesulphonyl)-pyrrolidin-3-yl]-indol-1-yl}-
    acetamide
    93 n-butyl 2-phenoxy-propionyl 1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-phenoxy-
    propan-1-one
    94 methyl-naphthyl 2-chloro-6-fluoro-3- (6-chloro-2-fluoro-3-methyl-phenyl)-[3-(1-naphthalen-2-
    methyl-benzoyl ylmethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
    95 2-propenyl 4-trifluoro-methyl-2- [3-(1-allyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-methyl-6-
    methyl-nicotinoyl trifluoromethyl-pyridin-3-yl)-methanone
    96 n-butyl 4-propyl-benzoyl [3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-propyl-
    phenyl)-methanone
    97 2-N,N-dimethyl- 4-chloro-benzoyl 2-{3-[1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-indol-1-yl}-
    acetamide N,N-dimethyl-acetamide
    98 3-fluoro-benzyl 3-phenyl-propionyl 1-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-
    yl}-3-phenyl-propan-1-one
    99 2-fluoro-benzyl 1-phenyl-5-propyl-1H- {3-[1-(2-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-
    pyrazol-4-carbonyl (1-phenyl-5-propyl-1H-pyrazol-4-yl)-methanone
    100 3-cyanobenzyl 5-tert-butyl-2-methyl- 3-{3-[1-(5-tert-butyl-2-methyl-furan-3-carbonyl)-
    furan-3-carbonyl pyrrolidin-3-yl]-indol-1-ylmethyl)-benzonitrile
    101 2-fluorobenzyl 2,4-difluorosulphanyl 3-[1-(2,4-difluoro-benzenesulphonyl)-pyrrolidin-3-yl]-1-
    (2-fluoro-benzyl)-1H-indol
    102 2-N,N-dimethyl- 2,6-difluoro-benzyl- 2-{3-[1-(2,6-difluoro-benzoyl)-pyrrolidin-3-yl]-indol-1-
    acetamide sulphanyl yl}-N,N-dimethyl-acetamide
    103 n-butyl butyryl 1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-butan-1-
    one
    104 4-cyanobenzyl 2-propyl-pentanoyl 4-{3-[1-(2-propyl-pentanoyl)-pyrrolidin-3-yl]-indol-1-
    ylmethyl)-benzonitrile
    105 2-propinyl (4-chloro-phenoxy)- 2-(4-chloro-phenoxy)-1-[3-(1-prop-2-ynyl-1H-indol-3-
    acetyl yl)-pyrrolidin-1-yl]-ethanone
    106 methyl nicotinoyl [3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-pyridin-3-
    yl-methanone
    107 3-cyanobenzyl benzo[1,3]dioxol-5- 3-{3-[1-(benzo[1,3]dioxole-5-carbonyl)-pyrrolidin-3-yl]-
    carbonyl indol-1-ylmethyl}-benzonitrile
    108 n-butyl 2-chloro-5-trifluoro- [3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-chloro-5-
    methyl-benzyl trifluoromethyl-phenyl)-methanone
    109 4-trifluoromethyl 3-chloro-benzoyl (3-chloro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-
    benzyl indol-3-yl]-pyrrolidin-1-yl}-methanone
    110 2-N,N-dimethyl- 4-bromo-benzoyl 2-{3-[1-(4-bromo-benzoyl)-pyrrolidin-3-yl]-indol-1-yl}-
    acetamide N,N-dimethyl-acetamide
    111 2-propinyl 3-phenyl-acryloyl 3-phenyl-1-[3-(1-prop-2-ynyl-1H-indol-3-yl)-pyrrolidin-
    1-yl]-propenone
    112 3-cyano-benzyl 3-chloro-2-fluoro- 3-{3-[1-(3-chloro-2-fluoro-benzoyl)-pyrrolidin-3-yl]-
    benzoyl indol-1-ylmethyl}-benzonitrile
    113 3-cyano-benzyl 2-phenyl-cyclopropan- 3-{3-[1-(2-phenyl-cyclopropanecarbonyl)-pyrrolidin-3-
    carbonyl yl]-indol-1-ylmethyl}-benzonitrile
    114 3-cyano-benzyl 3-chloro-thiophen-2- 3-{3-[1-(3-chloro-thiophen-2-carbonyl)-pyrrolidin-3-yl]-
    carbonyl indol-1-ylmethyl}-benzonitrile
    115 2-propinyl 2-trifluoromethyl- 1-prop-2-ynyl-3-[1-(2-trifluoromethyl-
    benzyl-sulphanyl benzenesulphonyl)-pyrrolidin-3-yl]-1H-indole
    116 2-fluorobenzyl 3-trifluoro-methyl- 1-(2-fluoro-benzyl)-3-[1-(3-trifluoromethyl-
    benzyl-sulphanyl benzenesulphonyl)-pyrrolidin-3-yl]-1H-indole
    117 benzyl 6-chloro-2H-chromen-3- [3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(6-chloro-2H-
    carbonyl chromen-3-yl)-methanone
    118 benzyl 3,4-difluoro-benzoyl [3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(3,4-difluoro-
    phenyl)-methanone
    • Example 2 Biological Testing
  • a) Tests on Serotonin Reuptake Inhibition
  • (5HT Uptake Inhibition)
  • In order to be able to carry out these in vitro studies, synaptosomes from rats' cerebral cortices were freshly isolated. A “P2” fraction prepared according to Gray and Whittaker's instructions (E. G. Gray and V. P. Whittaker (1962) J. Anat. 76, 79-88) was used in each case. These vesicular particles were isolated from the hypothalamus of male rats' brains for 5HT uptake.
  • A detailed description of the method may be found in the literature (M.Ch. Frink, H.-H. Hennies, W. Englberger, M. Haurand and B. Wilffert (1996) Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036).
  • b) Tests on Noradrenalin Reuptake Inhibition
  • (NA Uptake Inhibition)
  • In order to be able to carry out these in vitro studies, synaptosomes from rats' cerebral cortices were freshly isolated. A “P2” fraction, prepared according to Gray and Whittaker's instructions (E. G. Gray and V. P. Whittaker (1962) J. Anat. 76, 79-88) was used in each case. These vesicular particles were isolated from the hypothalamus of male rats' brains for NA uptake.
  • A detailed description of the method may be found in the literature (M.Ch. Frink, H.-H. Hennies, W. Englberger, M. Haurand and B. Wilffert (1996) Arzneim.-Frosch./Drug Res. 46 (III), 11, 1029-1036).
  • c) Binding Tests on the Sodium Channel
  • Binding Site 2 (BTX Bond):
  • The binding site 2 of the sodium channel is what is known as the batrachotoxin (BTX) binding site. [3H]-batrachotoxinin A20 α-benzoate (10 nM in a batch) was used as the ligand. These ion channel particles (synaptosomes) were enriched from rat cerebrocortex according to Gray and Whittaker (E. G. Gray and V. P. Whittaker (1962) J. Anat. 76, 79-88). The radioactivity measured in the presence of veratridine (0.3 mM in a batch) is defined as the unspecific bond. Incubation was carried out at 25° C. for 120 min. The assay conditions were adopted according to the publication by Pauwels, Leysen and Laduron (P. J. Pauwels, J. E. Leysen and P. M. Laduron (1986) Eur. J. Pharmacol. 124 291-298).
  • The KD value for this binding site is 24.63±1.56 nM. (N=3, i.e. mean±SEM from 3 independent test series which were carried out in triple parallel tests).
  • a) Inhibition of Serotonin Reuptake
    5HT uptake,
    Compound % inhibition [10 μM]
    17 43
    18 49
    19 86
    20 89
    21 84
    22 58
    23 49
    24 53
    25 80
    26 62
    27 70
    28 41
    29 63
    30 47
    31 62
    33 87
    34 57
    35 68
    36 42
    37 64
    39 43
    40 66
    41 44
    42 82
    43 48
    44 60
    45 80
    46 46
    47 46
    48 43
    49 68
    50 83
    52 79
    53 55
  • b) Inhibition of Noradrenalin Reuptake
    NA-uptake,
    Compound inhibition [10 μM]
    16 50
    18 49
    20 43
    24 59
    26 44
    28 52
    31 41
    32 44
    34 49
    35 48
    37 43
    38 49
    39 41
    40 43
    41 43
    42 58
    44 49
    45 43
    46 20
    48 40
    49 100
    51 57
    52 54
  • c) Binding to Binding Site 2 of the Sodium Channel
    BTX bond,
    % inhibition
    Compound [10 μM]
    1 95
    2 93
    3 93
    4 92
    5 92
    6 91
    7 89
    8 88
    9 84
    10 83
    11 83
    12 83
    13 82
    14 80
    15 80
    20 91
    26 93
    31 92
    33 89
    34 91
    35 84
    36 96
    38 89
    39 90
    42 96
    43 92
    45 82
    46 88
  • The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations falling within the scope of the appended claims and equivalents thereof.

Claims (20)

1. A substituted 3-pyrrolidine-indole compound corresponding to formula I
Figure US20050096376A1-20050505-C00011
wherein
the radical R1 represents H; respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-8-alkyl; respectively singly or multiply substituted or unsubstituted aryl bound via C1-3-alkyl, C3-8-cycloalkyl or heteroaryl; or CH2CONR3R4;
the radical R2 represents COR5; SO2R6; CSNHR7; CONHR8; or CH2CONHR9;
the radicals R3 and R4 independently of one another represent respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-8-alkyl;
or
the radicals R3 and R4 together represent CH2CH2OCH2CH2, or (CH2)3-6;
the radical R5 represents branched or unbranched, saturated or unsaturated, substituted or unsubstituted C1-8-alkyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; respectively saturated or unsaturated, substituted or unsubstituted cycloalkyl or heterocyclyl;
or
Figure US20050096376A1-20050505-C00012
where n=1,2,3; m=0, 1; X═O or NH and
Figure US20050096376A1-20050505-C00013
has the meaning of a single bond or a double bond;
the radical R6 represents respectively substituted or unsubstituted aryl, respectively substituted or unsubstituted heteroaryl, respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-8-alkyl; substituted or unsubstituted, saturated or unsaturated C3-8-cycloalkyl; or respectively singly or multiply substituted or unsubstituted aryl bound via C1-3-alkyl, C3-8-cycloalkyl or heteroaryl;
the radical R7 represents respectively substituted or unsubstituted aryl, respectively substituted or unsubstituted heteroaryl, respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-8-alkyl; substituted or unsubstituted, saturated or unsaturated C3-8 cycloalkyl; or respectively singly or multiply substituted or unsubstituted aryl bound via C1-3-alkyl, C3-8-cycloalkyl or heteroaryl;
the radical R8 represents branched or unbranched, substituted or unsubstituted, saturated or unsaturated C1-8-alkyl; substituted or unsubstituted, saturated or unsaturated C3-8-cycloalkyl; respectively singly or multiply substituted or unsubstituted trifluoromethyl- or nitrosubstituted phenyl, pyrrolyl, indolyl, furyl, benzofuranyl, thienyl, benzothienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazoyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, oxadiazolyl, chromenyl or phenothiazinyl; or respectively singly or multiply substituted or unsubstituted aryl bound via C1-3-alkyl, C3-8-cycloalkyl or heteroaryl;
the radical R9 represents branched or unbranched, substituted or unsubstituted, saturated or unsaturated C1-8-alkyl; substituted or unsubstituted, saturated or unsaturated C3-8-cycloalkyl; trifluoromethyl- or nitrosubstituted phenyl; respectively singly or multiply substituted or unsubstituted pyrrolyl, indolyl, furyl, benzofuranyl, thienyl, benzothienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazoyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, chromenyl, oxadiazolyl or phenothiazinyl; or respectively singly or multiply substituted or unsubstituted aryl bound via C1-3-alkyl, C3-8-cycloalkyl or heteroaryl;
R10 represents H; branched or unbranched, substituted or unsubstituted, saturated or unsaturated C1-8-alkyl; respectively substituted or unsubstituted aryl or heteroaryl, respectively substituted or unsubstituted benzyl or phenethyl and
R11 represents H; branched or unbranched, substituted or unsubstituted, saturated or unsaturated C1-8-alkyl; respectively substituted or unsubstituted aryl or heteroaryl, or respectively singly or multiply substituted or unsubstituted aryl bound via C1-3-alkyl, C3-8-cycloalkyl or heteroaryl;
or a salt thereof with a physiologically acceptable acid.
2. A substituted 3-pyrrolidine-indole compound according to claim 1, wherein said compound is present in the form of a base.
3. A substituted 3-pyrrolidine-indole compound according to claim 1, wherein said compound is present in the form of an individual enantiomer or diastereoisomer.
4. A substituted 3-pyrrolidine-indole compound according to claim 1, wherein said compound is present in the form of a mixture of stereoisomers.
5. A substituted 3-pyrrolidine-indole compound according to claim 1, wherein said compound is present in the form of a racemic mixture.
6. A substituted 3-pyrrolidine-indole compound according to claim 1, wherein the radical R2 represents COR5, SO2R6 or CSNHR7.
7. A substituted 3-pyrrolidine-indole compound according to claim 1, wherein the radical R2 represents CONHR8 or CH2CONHR9.
8. A substituted 3-pyrrolidine-indole compound according to claim 1, wherein the radical R1 represents H; respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-8-alkyl; respectively singly or multiply substituted or unsubstituted benzyl or methylnaphthyl; or CH2CONR3R4.
9. A substituted 3-pyrrolidine-indole compound according to claim 1, wherein the radical R1 represents benzyl which is unsubstituted or singly or multiply substituted by CF3, Br, F, CN, OCH3 or CH3.
10. A substituted 3-pyrrolidine-indole compound according to claim 1, wherein the radical R2 represents COR5 and R5 represents 4-propylphenyl, 3,4-dimethoxyphenyl, 2-methyl-4-trifluoromethylphenyl-3-pyridine, ethenylphenyl, 2,3-difluorophenyl, 4-tert.-butylphenyl, 2-ethoxyphenyl, 3-fluoro-4-trifluoromethylphenyl, 2,3-dimethylphenyl, phenoxyethyl, phenoxymethyl, 3,4dichlorophenyl, 4-trifluoromethylsulphanylphenyl, 2,5-dimethoxyphenyl, 2-chloro-4-nitrophenyl, 2-chlorophenyl, 4-methyl-N-phenethyl-benzylsulphonamide, 2-chloro-5-fluoro-3-methylphenyl, 3-(2-chlorophenyl)-5-methyl-isoxazole, 5-tert.-butyl-2-methylfuran,-benzo[1,2,5]oxadiazole, phenylpropyl, 2-methylsulphanyl-3-pyridine, 2-chloro-5 trifluoromethylphenyl, methoxymethyl, 4-methylphenyl, biphenyl, 4-chlorobenzyl, 2,3,4,5,6-pentafluorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl, 2,6-difluoro-3-methylphenyl, 2-methylphenyl, 4-fluorophenyl, 6-chlorochromene, 2-chloro-6-fluorophenyl, ethyl cyclopentyl, 1-(4-chlorophenyl)-5-trifluoromethylpyrazole, 2,4-dichlorophenyl, 2,3-dimethylphenyl, 3-nitro-4-methylphenyl, 4-bromo-3-methylphenyl, (4-chlorophenoxy)methyl, 4-chlorophenyl, 5-methylisoxazole, 3-methoxyphenyl, 2-chlorophenylethenyl, 2-chloro-4-fluoro-3-methylphenyl, 2-fluorophenyl, 3-difluoromethylsulphanylphenyl, 2-fluoro-3-chlorophenyl, cyclopropylphenyl, 1-phenyl-5propylpyrazole, 2,6-difluorophenyl, benzo[1,3]-dioxole, 4-bromophenyl, 3-chlorothiophenyl, 2-, 3- or 4-pyridine, phenyl or 3,4-difluorophenyl.
11. A substituted 3-pyrrolidine-indole compound according to claim 1, whrein the radical R2 represents SO2R6 and R6 represents 2,4,6-dimethylphenyl, 4-nitrophenyl, benzyl, 4-propylphenyl, 4-chlorophenyl, 2trifluoromethylphenyl, 2,4-difluorophenyl or 3-trifluoromethylphenyl.
12. A substituted 3-pyrrolidine-indole compound according to claim 1, wherein the radical R2 represents CSNHR7 and the radical R7 represents 3-trifluoromethylphenyl.
13. A substituted 3-pyrrolidine-indole compound according to claim 1, wherein the radical R2 represents CONHR8 and the radical R8 represents 3,4-dichlorobenzyl.
14. A substituted 3-pyrrolidine-indole compound according to claim 1, wherein the radical R2 represents CH2COR9 and R9 represents 2,5-dimethylpyrazole, 3-cyano-4-methylthiophene, 4-trifluoromethylphenyl, or 4-phenyl-5-trifluoromethylthiophene.
15. A substituted 3-pyrrolidine-indole compound according to claim 1, wherein said compound is selected from the group consisting of:
(4-propyl-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
(3,4-dimethoxy-phenyl)-{3-[1-(3-methyl-butyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-methanone
1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-3-phenyl-propenone
(2,3-difluoro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
(4-tert-butyl-phenyl)-{3-[1-(3-methyl-butyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
{3-[1-(4-bromo-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-(4-propyl-phenyl)-methanone
(2-ethoxy-phenyl)-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(3-fluoro-4-trifluoromethyl-phenyl)-methanone
(2,3-dimethyl-phenyl)-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-2-phenoxy-propan-1-one
2-(3-chloro-phenoxy)-1-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-ethanone
4-{3-[1-(2-phenoxy-propionyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
N,N-dimethyl-2-{3-[1-(2,4,6-trimethyl-benzenesulphonyl)-pyrrolidin-3-yl]-indol-1-yl}-acetamide
(3,4-dichloro-phenyl)-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
N,N-dimethyl-2-{3-[1-(3-trifluoromethyl-phenylthiocarbamoyl)-pyrrolidin-3-yl]-indol-1-yl}-acetamide
3-(1-dimethylcarbanmoylmethyl-1H-indol-3-yl)-pyrrolidin-1-carboxylic acid 3,4-dichloro-benzylamide
[3-(1H-indol-3-yl)-pyrrolidin-1-yl]-(4-trifluoromethylsulphanyl-phenyl)-methanone
2-(3-{1-[2-(2,5-dimethoxy-phenyl)-acetyl]-pyrrolidin-3-yl}-indol-1-yl)-N,N-dimethyl-acetamide
(2-chloro-4-nitro-phenyl)-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
N,N-dimethyl-2-{3-[1-(pyridin-2-carbonyl)-pyrrolidin-3-yl]-indol-1-yl}-acetamide
cyclobutyl-[3-(1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
N,N-diethyl-2-[3-(1-pentanoyl-pyrrolidin-3-yl)-indol-1-yl]-acetamide
3-[1-(4-nitrobenzenesulphonyl)-pyrrolidin-3-yl]-1H-indole
2-[3-(1-cyclopentanecarbonyl-pyrrolidin-3-yl)-indol-1-yl]-N,N-diethyl-acetamide
1-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3-phenyl-propenone
(2-chloro-phenyl)-[3-(1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-pyridin-3-yl-methanone
N,N-dimethyl-2-(3-{1-[3-phenyl-2-(toluene-4-sulphonylamino)-propionyl]-pyrrolidin-3-yl}-indol-1-yl)-acetamide
N,N-dimethyl-2-[3-(1-phenylmethanesulphonyl-pyrrolidin-3-yl)-indol-1-yl]-acetamide
4-{3-[1-(2-chloro-6-fluoro-3-methyl-benzoyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
[3-(2-chloro-phenyl)-5-methyl-isoxazol-4-yl]-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1yl]-methanone
2-{3-[1-(5-tert-butyl-2-methyl-furan-3-carbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
4-{3-[1-(benzo[1,2,5]oxadiazole-5-carbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
1-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3-phenyl-propan-1-one
1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-3-phenyl-propan-1-one
[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-methylsulphanyl-pyridin-3-yl)-methanone
(2-chloro-5-trifluoromethyl-phenyl)-[3-(1-ethyl-i H-indol-3-yl)-pyrrolidin-1-yl]-methanone
(2-chloro-4-nitro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1 yl}-methanone
(2-chloro-pyridin-3-yl)-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
2-methoxy-1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-ethanone
{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-(2-methyl-6-trifluoromethylpyridin-3-yl)-methanone
{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-p-tolyl-methanone
(2-methylsulphanyl-pyridin-3-yl)-[3-(1-prop-2-ynyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
biphenyl-4-yl-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
2-(4-chloro-phenyl)-1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-ethanone
[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-pentafluorophenyl-methanone
[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-trifluoromethyl-phenyl)-methanone
2-[3-(1-but-2-ynyl-1H-indol-3-yl)-pyrrolidin-1-yl]-N-(2,5-dimethyl-2H-pyrazol-3-yl)-acetamide
N-(3-cyano-4-methyl-thiophen-2-yl)-2-{3-[1-(3,5-dimethyl-benzyl)-1H-indol-3-yl]pyrrolidin-1-yl}-acetamide
N,N-diethyl-2-(3-{1-[(4-trifluoromethyl-phenyl carbamoyl)-methyl]-pyrrolidin-3-yl}-indol-1-yl)-acetamide
N-(3-cyano-4-methyl-thiophen-2-yl)-2-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-acetamide
2-{3-[1-(3,4-difluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-N-(4-phenyl-5-trifluoromethyl-thiophen-3-yl)-acetamide
N,N-dimethyl-2-{3-[1-(4-propyl-benzenesulphonyl)-pyrrolidin-3-yl]-indol-1-yl}-acetamide
(2-chloro-4-nitro-phenyl)-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
3-{3-[1-(4-chloro-benzenesulphonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
1-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-3,3-dimethyl-butan-1-one
2-(4-chloro-phenyl)-1-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-ethanone
(2,6-difluoro-3-methyl-phenyl)-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-o-tolyl-methanone
[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-fluoro-phenyl)-methanone
[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(6-chloro-2H-chromen-3-yl)-methanone
(2-chloro-6-fluoro-phenyl)-[3-(1-naphthalen-2-ylmethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
2-{3-[1-(3-cyclopentyl-propionyl)-pyrrolidin-3-yl]-indol-1-yl}-N,N-dimethyl-acetamide
[3-(2-chloro-phenyl)-5-methyl-isoxazol-4-yl]-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
[3-(1-allyl-1H-indol-3-yl)-pyrrolidin-1-yl]-p-tolyl-methanone
{3-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-pyridin-2-yl-methanone
(3,4-dichloro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
1-butyl-3-[1-(2,5-dimethoxy-benzenesulphonyl)-pyrrolidin-3-yl]-1H-indole
1-[3-(1-allyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3,3-dimethyl-butan-1-one
4-{3-[1-(2-methoxy-acetyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
(2,4-difluoro-phenyl)-[3-(1-ethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
(2,3-dimethyl-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-methyl-3-nitro-phenyl)-methanone
(4-bromo-3-methyl-phenyl)-{3-[1-(3-methoxy-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-(4-chloro-phenoxy)-ethanone
2-(4-chloro-phenyl)-1-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-ethanone
(4-chloro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
[3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(5-methyl-isoxazol-3-yl )-methanone
1-[3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-(4-chloro-phenoxy)-ethanone
[3-(1-naphthalen-2-ylmethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-trifluoromethylphenyl)-methanone
(3-methoxy-phenyl)-(3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-3-(2-chloro-phenyl)-propenone
1-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-phenyl-butane-1-one
(2-chloro-6-fluoro-3-methyl-phenyl)-[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
2-{3-[1-(3-methoxy-benzoyl)-pyrrolidin-3-yl]-indol-1-yl}-N,N-dimethyl-acetamide
2-{3-[1-(2-fluoro-benzoyl)-pyrrolidin-3-yl]-indol-1-yl}-N,N-dimethyl-acetamide
(3-difluoromethylsulphanyl-phenyl)-[3-(1-naphthalen-2-ylmethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
benzo[1,2,5]oxadiazol-5-yl-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
o-tolyl-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
N,N-dimethyl-2-{3-[1-(2-trifluoromethyl-benzenesulphonyl)-pyrrolidin-3-yl]-indol-1-yl}-acetamide
1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-2-phenoxy-propan-1-one
(6-chloro-2-fluoro-3-methyl-phenyl)-[3-(1-naphthalen-2-ylmethyl-1H-indol-3-yl)-pyrrolidin-1-yl]-methanone
[3-(1-allyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-methanone
[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(4-propyl-phenyl)-methanone
2-{3-[1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-indol-1-yl)-N,N-dimethyl-acetamide
1-{3-[1-(3-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-3-phenyl-propan-1-one
{3-[1-(2-fluoro-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-(1-phenyl-5-propyl-1H-pyrazol-4-yl)-methanone
3-{3-[1-(5-tert-butyl-2-methyl-furan-3-carbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
3-[1-(2,4-difluoro-benzenesulphonyl)-pyrrolidin-3-yl]-1-(2-fluoro-benzyl)-1H-indole
2-{3-[1-(2,6-difluoro-benzoyl)-pyrrolidin-3-yl]-indol-1-yl}-N,N-dimethyl-acetamide
1-[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-butane-1-one
4-{3-[1-(2-propyl-pentanoyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
2-(4-chloro-phenoxy)-1-[3-(1-prop-2-ynyl-1H-indol-3-yl)-pyrrolidin-1-yl]-ethanone
[3-(1-methyl-1H-indol-3-yl)-pyrrolidin-1-yl]-pyridin-3-yl-methanone
3-{3-[1-(benzo[1,3]dioxole-5-carbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
[3-(1-butyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(2-chloro-5-trifluoromethyl-phenyl)-methanone
(3-chloro-phenyl)-{3-[1-(4-trifluoromethyl-benzyl)-1H-indol-3-yl]-pyrrolidin-1-yl}-methanone
2-{3-[1-(4-bromo-benzoyl)-pyrrolidin-3-yl]-indol-1-yl}-N,N-dimethyl-acetamide
3-phenyl-1-[3-(1-prop-2-ynyl-1H-indol-3-yl)-pyrrolidin-1-yl]-propenone
3-{3-[1-(3-chloro-2-fluoro-benzoyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
3-{3-[1-(2-phenyl-cyclopropanecarbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
3-{3-[1-(3-chloro-thiophene-2-carbonyl)-pyrrolidin-3-yl]-indol-1-ylmethyl}-benzonitrile
1-prop-2-ynyl-3-[1-(2-trifluoromethyl-benzenesulphonyl)-pyrrolidin-3-yl]-1H-indole
1-(2-fluoro-benzyl)-3-[1-(3-trifluoromethyl-benzenesulphonyl)-pyrrolidin-3-yl]-1H-indole
[3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(6-chloro-2H-chromen-3-yl)-methanone
[3-(1-benzyl-1H-indol-3-yl)-pyrrolidin-1-yl]-(3,4-difluoro-phenyl)-methanone
16. A pharmaceutical composition for treating pain, depression, cardiovascular diseases, urinary incontinence diarrhea, pruritus, alcohol abuse, drug abuse, substance dependency, inflammations, lethargy, bulimia, anorexia, catalepsy; for use as a local anaesthetic, an anti-arrhythmic, an anti-emetic or a nootropic; for increasing alertness or libido or for anxiolysis comprising as an active ingredient a pharmaceutically effective amount of a 3-pyrrolidine-indole compound corresponding to formula I of claim 1 and one or more suitable additives or auxiliaries.
17. The pharmaceutical composition of claim 16, wherein said pain is acute, neuropathic or chronic pain.
18. A method of alleviating pain, depression, cardiovascular diseases, urinary incontinence diarrhea, pruritus, alcohol abuse, drug abuse, substance dependency, inflammations, lethargy, bulimia, anorexia, catalepsy; for providing a local anaesthesia, an anti-arrhythmic, an anti-emetic or a nootropic; for increasing alertness or libido or for anxiolysis in a mammal said method comprising administering to said mammal a pharmaceutically effective amount of a 3-pyrrolidine-indole compound corresponding to formula I of claim 1.
19. The method of claim 18, wherein said pain is acute, neuropathic or chronic pain.
20. A method for producing a substituted 3-pyrrolidine-indole compound corresponding to formula I of claim 1, starting from 3-pyrrolidin-3-yl-indole, comprising the steps of:
a) providing the pyrrolidine nitrogen of 3-pyrrolidin-3-yl-indole with a protecting group;
b) alkylating the indole nitrogen;
c) removing the protecting group and
d) reacting the pyrrolidine nitrogen with a 2-chloroacetamide or a 2-bromoacetamide, an acid chloride, an isocyanate or an isothiocyanate.
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007010964A1 (en) * 2005-07-22 2007-01-25 Shionogi & Co., Ltd. Indole derivative having pgd2 receptor antagonist activity
US20080021022A1 (en) * 2006-07-20 2008-01-24 Amgen Inc. Substituted azole aromatic heterocycles as inhibitors of 11beta-hsd-1
US20090105274A1 (en) * 2005-09-06 2009-04-23 Akira Kugimiya Indolecarboxylic Acid Derivative Having PGD2 Receptor Antagonistic Activity
US20100267761A1 (en) * 2007-11-05 2010-10-21 Merck Patent Gesellschaft 7-Azaindole Derivatives as Selective 11-Beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitors
US7842692B2 (en) 2005-07-22 2010-11-30 Shionogi & Co., Ltd. Azaindole derivative having PGD2 receptor antagonistic activity
CN102702175A (en) * 2012-06-21 2012-10-03 东华大学 Preparation method of indole-3-succinimide
CN102942560A (en) * 2012-12-04 2013-02-27 东华大学 Preparation method of 3-(2-methylindolyl-3-)pyrryl-2,5-dione
US9725442B2 (en) 2011-10-25 2017-08-08 Shionogi & Co., Ltd. Heterocyclic derivative having PGD2 receptor antagonist activity
US10533014B2 (en) 2014-11-05 2020-01-14 Flexus Biosciences, Inc. Immunoregulatory agents
US11242319B2 (en) 2014-11-05 2022-02-08 Flexus Biosciences, Inc. Immunoregulatory agents

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005066157A1 (en) * 2004-01-02 2005-07-21 Suven Life Sciences 3-(pyrolidin-3-l) indoles as 5-ht6 receptor modulators
MY145694A (en) * 2005-04-11 2012-03-30 Xenon Pharmaceuticals Inc Spiroheterocyclic compounds and their uses as therapeutic agents
MY144968A (en) 2005-04-11 2011-11-30 Xenon Pharmaceuticals Inc Spiro-oxindole compounds and their uses as therapeutic agents
CL2007002950A1 (en) 2006-10-12 2008-02-01 Xenon Pharmaceuticals Inc USE OF COMPOUNDS DERIVED FROM ESPIRO-OXINDOL IN THE TREATMENT OF HYPERCHOLESTEROLEMIA, BENIGNA HYPERPLASIA DE PROSTATA, PRURITIS, CANCER
CN101522685A (en) * 2006-10-12 2009-09-02 泽农医药公司 Tricyclic spiro-oxindole derivatives and their uses as therapeutic agents
TW200825091A (en) * 2006-10-12 2008-06-16 Xenon Pharmaceuticals Inc Spiro-oxindole compounds useful in treating sodium channel-mediated diseases or conditions
UA100684C2 (en) * 2007-03-15 2013-01-25 Новартіс Аг Normal;heading 1;heading 2;heading 3;BENZYL AND PYRIDINYL DERIVATIVES AS MODULATORS OF THE HEDGEHOG SIGNALING PATHWAY
US20100041663A1 (en) 2008-07-18 2010-02-18 Novartis Ag Organic Compounds as Smo Inhibitors
WO2010045197A1 (en) 2008-10-17 2010-04-22 Xenon Pharmaceuticals, Inc. Spiro-oxindole compounds and their use as therapeutic agents
RU2011119626A (en) 2008-10-17 2012-11-27 Ксенон Фармасьютикалз Инк. SPIROOXINDOL COMPOUNDS AND THEIR APPLICATION AS A THERAPEUTIC
AR077252A1 (en) 2009-06-29 2011-08-10 Xenon Pharmaceuticals Inc ESPIROOXINDOL COMPOUND ENANTIOMERS AND THEIR USES AS THERAPEUTIC AGENTS
RU2015103694A (en) 2009-10-14 2015-06-27 Ксенон Фармасьютикалз Инк. METHODS FOR SYNTHESIS OF SPIRO-OXINDOL COMPOUNDS
US20110086899A1 (en) * 2009-10-14 2011-04-14 Xenon Pharmaceuticals Inc. Pharmaceutical compositions for oral administration
CN102946859B (en) 2010-02-26 2016-03-02 泽农医药公司 For the pharmaceutical composition of the spiral shell-oxindole compounds of topical and the purposes as therapeutic agent thereof
US10092574B2 (en) 2012-09-26 2018-10-09 Valorisation-Recherche, Limited Partnership Inhibitors of polynucleotide repeat-associated RNA foci and uses thereof
TW201636017A (en) 2015-02-05 2016-10-16 梯瓦製藥國際有限責任公司 Methods of treating postherpetic neuralgia with a topical formulation of a spiro-oxindole compound
WO2024026574A1 (en) * 2022-08-05 2024-02-08 Mindset Pharma Inc. 3-pyrrolidine-indole dimers as serotonergic agents useful for the treatment of disorders related thereto

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3109844A (en) * 1959-09-16 1963-11-05 Bristol Myers Co 3-(3-indolyl) pyrrolidines
US5792760A (en) * 1997-04-23 1998-08-11 Eli Lilly And Company Bisindoles as tachykinin receptor antagonists
US5891875A (en) * 1996-05-20 1999-04-06 Eli Lilly And Company Morpholinyl tachykinin receptor antagonists
US6777437B2 (en) * 2001-03-29 2004-08-17 Bristol-Myers Squibb Company Cyclopropylindole derivatives as selective serotonin reuptake inhibitors
US20050171143A1 (en) * 2002-05-16 2005-08-04 Norihiko Tanimoto Compound exhibiting pgd 2 receptor antagonism

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE190608T1 (en) 1991-11-25 2000-04-15 Pfizer 5-(HETERO- OR CARBOCYCLYLAMINO)-INDOLE DERIVATIVES, THEIR PRODUCTION AND THEIR USE AS 5-HT1 AGONISTS
TW251284B (en) 1992-11-02 1995-07-11 Pfizer
GB9420529D0 (en) * 1994-10-12 1994-11-30 Pfizer Ltd Indoles
DE19615232A1 (en) * 1996-04-18 1997-10-23 Merck Patent Gmbh New carbamoyl derivatives and their use as 5-HT ¶1¶¶A¶ antagonists
EP0897921A1 (en) 1997-08-22 1999-02-24 Eli Lilly And Company Limited Benzothiadiazinyl-indole derivatives and their use as serotonin receptor ligands
DE19756036A1 (en) * 1997-12-17 1999-06-24 Merck Patent Gmbh New indole amide derivatives
GB9810886D0 (en) 1998-05-13 1998-07-22 Lilly Industries Ltd Pharmaceutical compounds
NL1012754C2 (en) * 1999-07-30 2001-02-01 Presstech N V Pressure control device.
US6476051B2 (en) 1999-12-17 2002-11-05 Bristol-Myers Squibb Company Antipsychotic heterocycle compounds
ES2262674T3 (en) 2000-08-14 2006-12-01 Ortho-Mcneil Pharmaceutical, Inc. REPLACED PIRAZOLS.
HUP0400684A2 (en) * 2000-12-22 2004-07-28 Wyeth Heterocyclindazole and azaindazole compounds as 5-hydroxytryptamine-6 ligands, their preparation and pharmaceutical compositions containing them
WO2002079151A1 (en) 2001-03-29 2002-10-10 Smithkline Beecham P.L.C. 3-substituted indoels or fused pyrroles as antagonists of the chemokine mcp-1 (ccr2b) receptor
GB0107907D0 (en) 2001-03-29 2001-05-23 Smithkline Beecham Plc Novel compounds
DE10252666A1 (en) * 2002-11-11 2004-08-05 Grünenthal GmbH N-piperidyl-cyclohexane derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3109844A (en) * 1959-09-16 1963-11-05 Bristol Myers Co 3-(3-indolyl) pyrrolidines
US5891875A (en) * 1996-05-20 1999-04-06 Eli Lilly And Company Morpholinyl tachykinin receptor antagonists
US5792760A (en) * 1997-04-23 1998-08-11 Eli Lilly And Company Bisindoles as tachykinin receptor antagonists
US6777437B2 (en) * 2001-03-29 2004-08-17 Bristol-Myers Squibb Company Cyclopropylindole derivatives as selective serotonin reuptake inhibitors
US20050171143A1 (en) * 2002-05-16 2005-08-04 Norihiko Tanimoto Compound exhibiting pgd 2 receptor antagonism

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090030014A1 (en) * 2005-07-22 2009-01-29 Akira Kugimiya Indole Derivative Having Pgd2 Receptor Antagonist Activity
WO2007010964A1 (en) * 2005-07-22 2007-01-25 Shionogi & Co., Ltd. Indole derivative having pgd2 receptor antagonist activity
JP5072594B2 (en) * 2005-07-22 2012-11-14 塩野義製薬株式会社 Indole derivatives having PGD2 receptor antagonist activity
US7842692B2 (en) 2005-07-22 2010-11-30 Shionogi & Co., Ltd. Azaindole derivative having PGD2 receptor antagonistic activity
US20110028717A1 (en) * 2005-07-22 2011-02-03 Akira Kugimiya Azaindole derivative having pgd2 receptor antagonistic activity
US7956082B2 (en) 2005-07-22 2011-06-07 Shionogi & Co., Ltd Indole derivative having PGD2 receptor antagonist activity
US8143285B2 (en) 2005-09-06 2012-03-27 Shionogi & Co., Ltd. Indolecarboxylic acid derivative having PGD2 receptor antagonistic activity
US8623903B2 (en) 2005-09-06 2014-01-07 Shionogi & Co., Ltd. Indolecarboxylic acid derivative having PGD2 receptor antagonistic activity
US20090105274A1 (en) * 2005-09-06 2009-04-23 Akira Kugimiya Indolecarboxylic Acid Derivative Having PGD2 Receptor Antagonistic Activity
US7666888B2 (en) * 2006-07-20 2010-02-23 Amgen Inc. Substituted azole aromatic heterocycles as inhibitors of 11β-HSD-1
US20080021022A1 (en) * 2006-07-20 2008-01-24 Amgen Inc. Substituted azole aromatic heterocycles as inhibitors of 11beta-hsd-1
US20100267761A1 (en) * 2007-11-05 2010-10-21 Merck Patent Gesellschaft 7-Azaindole Derivatives as Selective 11-Beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitors
US8470849B2 (en) * 2007-11-05 2013-06-25 Merck Patent Gmbh 7-azaindole derivatives as selective 11-β-hydroxysteroid dehydrogenase type 1 inhibitors
US9725442B2 (en) 2011-10-25 2017-08-08 Shionogi & Co., Ltd. Heterocyclic derivative having PGD2 receptor antagonist activity
CN102702175A (en) * 2012-06-21 2012-10-03 东华大学 Preparation method of indole-3-succinimide
CN102942560A (en) * 2012-12-04 2013-02-27 东华大学 Preparation method of 3-(2-methylindolyl-3-)pyrryl-2,5-dione
US10533014B2 (en) 2014-11-05 2020-01-14 Flexus Biosciences, Inc. Immunoregulatory agents
US11242319B2 (en) 2014-11-05 2022-02-08 Flexus Biosciences, Inc. Immunoregulatory agents
US11932601B2 (en) 2014-11-05 2024-03-19 Flexus Biosciences, Inc. Immunoregulatory agents

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